Homozygous SMAD6 variants in two unrelated patients with craniosynostosis and radioulnar synostosis.

BACKGROUND: SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described. CASES: Here, we present the first two patients with craniosynostosis harbouring homozygous SMAD6 variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities. MOLECULAR ANALYSES: The novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a,817delins[a;817+2_817+228])];[(817g>a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action. CONCLUSION: Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.

Investigating the role connective tissue fibroblasts play in the altered muscle anatomy associated with the limb abnormality, Radial Dysplasia.

Radial dysplasia (RD) is a congenital upper limb birth defect that presents with changes to the upper limb anatomy, including a shortened or absent radius, bowed ulna, thumb malformations, a radially deviated hand and a range of muscle and tendon malformations, including absent or abnormally shaped muscle bundles. Current treatments to address wrist instability caused by a shortened or absent radius frequently require an initial soft tissue distraction intervention followed by a wrist stabilisation procedure. Following these surgical interventions, however, recurrence of the wrist deviation remains a common, long-term problem following treatment. The impact of the abnormal soft connective tissue (muscle and tendon) anatomy on the clinical presentation of RD and the complications following surgery are not understood. To address this, we have examined the muscle, fascia and the fascial irregular connective tissue (ICT) fibroblasts found within soft connective tissues, from RD patients. We show that ICT fibroblasts isolated from RD patients are functionally abnormal when compared to the same cells isolated from control patients and secrete a relatively disordered extracellular matrix (ECM). Furthermore, we show that ICT fibroblast dysfunction is a unifying feature found in RD patients, even when the RD clinical presentation is caused by distinct genetic syndromes.

A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia.

Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) type 2, caused by MDS1 and EVI1 complex locus (MECOM) gene mutations, is a rare inherited bone marrow failure syndrome (IBMFS) with skeletal anomalies, characterized by varying presentation of congenital thrombocytopenia (progressing to pancytopenia), bilateral proximal radioulnar synostosis, and other skeletal abnormalities. Due to limited knowledge and heterogenous manifestations, clinical diagnosis of the disease is challenging. Here we reported a novel MECOM mutation in a Chinese boy with typical clinical features for RUSAT-2. Trio-based whole exome sequencing of buccal swab revealed a novel heterozygous missense mutation in exon 11 of the MECOM gene (chr3:168818673; NM_001105078.3:c.2285G > A). The results strongly suggest that the variant was a germline mutation and disease-causing mutation. The patient received matched unrelated donor hematopoetic stem cell transplantation (HSCT). This finding was not only expanded the pathogenic mutation spectrum of MECOM gene, but also provided key information for clinical diagnosis and treatment of RUSAT-2.

Ulnar lengthening for children with forearm deformity from hereditary multiple exostoses: a retrospective study from a tertiary medical center.

BACKGROUND: Patients with hereditary multiple exostosis (HME) usually present with forearm deformity with or without radial head dislocation. Ulna lengthening has been proposed to address this condition. Exostosis resection plus ulna lengthening has been adopted in our hospital since 2008, and patients with this condition were retrospectively reviewed. Herein, we aimed to investigate the optimal timing and clinical outcomes of this surgical approach. METHODS: In all, thirty-five patients (40 forearms), including 22 boys and 13 girls, were enrolled in our study from July 2014 to September 2020. We divided the patients into 4 groups based on the age when they received surgery and the status of the radial head. Pronation and supination of the forearm, flexion and extension of the elbow, wrist ulnar deviation and wrist radial deviation, and radiological parameters including ulnar length (UL), ulnar variance (UV), the percentage of radial bowing (RB/RL), radio articular angle (RAA) and carpal slip (CS), were assessed and recorded. RESULTS: The mean UL was significantly improved after surgery in four Groups (P<0.05). In patients with radial head dislocation, we found significant improvement in forearm, wrist function and elbow flexion (p < 0.05). For the patients with radial head dislocation, the juniors demonstrated better improvement in % RB and RAA (p<0.05, p = 0.003 and 0.031). CONCLUSION: Exostosis resection and ulna lengthening with unilateral external fixation can effectively improve the function and radiological parameters of forearm deformity in HME children. For patients with radial head dislocation, early surgery can achieve better results. For patients not associated with radial head dislocation, we recommend regular follow-up and surgical treatment after 10 years of age.

Guided Growth With Minifragment Plates for Angular Deformities in the Distal Radius in Skeletally Immature Patients. Preliminary Results.

INTRODUCTION: Growth modulation allows correction of progressive ulnar deviation of the distal radius in skeletally immature patients, which may occur as a consequence of various pathologies. The aim of this study is to evaluate the radiographic results and complication rate in a series of patients treated with minifragment plates. METHODS: The medical records of 12 patients who underwent guided growth with a minifragment plate on the radial aspect of the distal radius as a consequence of angular deformities in the distal radius were retrospectively reviewed. Demographic data, radiographic changes, and complication rate were analyzed. RESULTS: A total of 14 wrists and forearms were evaluated. The mean age at which surgery was performed was 10.5 years (interquartile range: 9.0 to 11.3). The average time between placement and removal of the material was 28.7 months (SD: 8,89). In each case, a general improvement of the radiographic parameters was obtained. There were 3 postoperative complications, but only 1 of them required reintervention (broken metaphyseal screw). CONCLUSIONS: Hemiepiphysiodesis using a minifragment plate is a treatment that respects the surgical anatomy and offers an alternative surgical option for angular deformities of the distal radius in children. LEVEL OF EVIDENCE: Level IV.

Reconstruction of congenital pseudarthrosis of the radius with a vascularized tibial periosteal transplant: A case report.

Congenital pseudarthrosis of the forearm poses a considerable challenge because of its rarity. The objective of this report is to introduce a novel surgical technique for its treatment. Here, we document a case of congenital pseudarthrosis of the radius in a 3-year-old boy diagnosed with type-1 neurofibromatosis. The surgical treatment involved the excision of approximately 9 cm of native radial periosteum and a bifocal radius osteotomy, which was supplemented with a vascularized tibial periosteal transplant to facilitate bone healing. Anastomosis between the anterior tibial vessels and radial vessels was performed. No immediate or late postoperative complications were observed. After 3 weeks, a robust callus formation was observed, and during a follow-up examination 3 years and 4 months later, a wide range of active forearm rotation was noted. This report suggests that vascularized periosteal flaps show promise as a viable treatment option for congenital pseudarthrosis of the forearm. They offer an alternative to vascularized fibular grafts or single-bone forearm constructs.

Effects of simulated radioulnar synostosis on supination and pronation in cats. A cadaveric study.

OBJECTIVE: To evaluate the effect of an induced synostosis with a screw on pronation and supination in cats. STUDY DESIGN: Ex vivo biomechanical study. SAMPLE POPULATION: A total of 58 feline forelimbs. METHODS: A total of 58 cadaveric feline thoracic limbs were mounted on a custom-built jig with the elbow and carpus flexed at a 90° angle. To exclude any orthopedic disease, radiographs of the forelimbs were performed prior to the mechanical tests. Radioulnar synostosis was imitated with a 2 mm cortical screw through the radius into the ulna in the proximal (Group P; n = 54), middle (Group M; n = 52), and distal (Group D; n = 53) radial diaphysis. The angles of pronation and supination were recorded after manually applying a two-finger tight rotational force to the metacarpus. Rotational tests were performed without a screw (Group N) and with a screw in each of the aforementioned positions. Pairwise comparisons between the groups were performed based on their angles of rotation with a paired t-test with the Benjamini-Hochberg procedure and a mixed model ANOVA. RESULTS: Mean angles of rotation decreased between Group N (129.5 ± 15.9°) and all groups with imitated radioulnar synostosis to a mean angle of 37.5 ± 14.5° (p < .0001). Mean angles of rotation did not differ between the groups with imitated radioulnar synostosis. CONCLUSION: Induced radioulnar synostosis decreases antebrachial rotation by more than two-thirds, regardless of location. CLINICAL SIGNIFICANCE: Implants fixating the radius to the ulna should be avoided in cats, regardless where they are located along the radial diaphysis.

Fetal hydrops caused by a novel pathogenic MECOM variant.

We report a fetus with hydrops, congenital heart disease and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. The female fetus was referred for post-mortem examination after fetal hydrops and intrauterine death was diagnosed at 20 weeks gestation. Post-mortem examination confirmed fetal hydrops, pallor, truncus arteriosus and bilateral radioulnar synostosis. Trio whole genome sequencing analysis detected a novel de novo heterozygous pathogenic loss-of-function variant in MECOM (NM_004991), associated with a diagnosis of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2). RUSAT-2 is a variable condition associated postnatally with bone marrow failure, radioulnar synostosis and congenital anomalies. RUSAT-2 is not currently associated with a prenatal phenotype or fetal demise, and was not present on diagnostic NHS prenatal gene panels at time of diagnosis. This case highlights the diagnostic value of detailed phenotyping with post-mortem examination, and of using a broad sequencing approach.

Congenital Proximal Radioulnar Synostosis in an Elite Athlete-Case Report.

Background and Objectives: Proximal radioulnar synostosis (PRUS) is the most frequent congenital forearm disorder, although the prevalence in the general population is rare with a few hundred cases reported. Pfeiffer, Poland, Holt-Oram, and other serious congenital syndromes contain this abnormality. Non-syndromic cases with isolated PRUS very often exhibit as SMAD6, NOG genes variants, or sex chromosome aneuploidy. A subgroup of patients with haematological abnormalities presents with HOXA11 or MECOM genes variants. Case report: We present a non-syndromic adult elite ice-hockey player with unilateral proximal radioulnar synostosis of the left forearm. In early childhood he was able to handle the hockey stick only as a right-handed player and the diagnosis was set later at the age of 8 years due to lack of supination. Cleary-Omer Type III PRUS was found on x-ray with radial head hypoplasia and mild osteophytic degenerative changes of humeroulnar joint. Since the condition had minimal impact on sports activities, surgical intervention was not considered. The player continued his ice-hockey career at the top level and joined a national team for top tournaments. Upper extremity function assessment with questionnaires and physical testing resulted in minimal impairment. The most compromised tool was the Failla score with 10 points from a total of 15. Genetic testing with Sanger sequencing revealed no significant pathogenic variant in SMAD6, NOG, and GDP5 genes. No potentially pathogenic copy number variants were detected by array-based comparative genomic hybridization. Conclusions: In the reported case, the ability of an athlete to deal with an anatomic variant limiting the forearm supination is demonstrated. Nowadays, a comprehensive approach to rule out more complex musculoskeletal impairment and family burden is made possible by evolving genetics.

Evaluation of the ulna lengthening by distraction osteogenesis in congenital radial deficiency.

PURPOSE: Publications evaluating the results of the ulna lengthening in congenital radial deficiency are based only on small groups of subjects which yield statistical studies of low scientific value. The aim was to examine the effectiveness of ulna lengthening in radial longitudinal deficiency and determine the number and quality of complications based on one of the most numerous study groups described in the literature. METHODS: The material consists of a study group with 31 upper limbs of unmatured patients diagnosed with type III and IV radial longitudinal deficiency. The study group was evaluated based on the parameters known from the literature. The difficulties during elongation were classified according to Paley's classification. RESULTS: The study group contained patients with a mean age of 9 years, and the number of boys and girls was comparable. Ulna length significantly increased after elongation compared to the initial bone length. The patient's age didn't affect the ulna lengthening, and the amount of elongation didn't significantly affect the total stabilization period. However, the total stabilization time increased with increasing patient age. Difficulties affected more than half of the cases. CONCLUSIONS: Ulna elongation in congenital radial deficiency results in significant lengthening of the ulna, and thus the entire forearm, compared to the initial bone length. This technique has a high percentage of difficulty, so its use should be considered after cautious discussion with the parents and patients.

MECOM-related disorder: Radioulnar synostosis without hematological aberration due to unique variants.

PURPOSE: The etiology for a considerable proportion of patients with congenital radioulnar synostosis (RUS) remains unclear. This study aimed to investigate the genetic cause of RUS without a known cause. METHODS: Patients with RUS were investigated. Exome sequencing and/or Sanger sequencing was performed. Bioinformatics analysis was also performed. Pathogenicity was evaluated for variants of interest. RESULTS: We identified unique missense variants in MECOM (encodes EVI1) associated with RUS in 8 families. Of them, 6 families had variants in residue R781, including 3 families with R781C (c.2341C>T), 2 families with R781H (c.2342G>A), and 1 family with R781L (c.2342G>T). Another 2 variants included I783T (c.2348T>C) in 1 family and Q777E (c.2329C>G) in 1 family. All these variants were clustered within the ninth zinc finger motif of EVI1. Phenotype evaluation identified that most of these patients with RUS harboring mutant MECOM had finger malformations, but none of them had identifiable hematological abnormalities. Functional experiments showed that MECOM R781C led to alterations in TGF-ß-mediated transcriptional responses. CONCLUSION: This study examined MECOM variants by focusing on RUS instead of hematological abnormalities. The R781 residue in EVI1 is a hotspot for human RUS variants. Mutant MECOM is the second most common cause for familial RUS.

Expanding the phenotypic spectrum of COLEC10-Related 3MC syndrome: A glimpse into COLEC10-Related 3MC syndrome in the Ashkenazi Jewish population.

Bi-allelic variants in COLEC11 and MASP1 have been associated with 3MC syndrome, a clinical entity made of up four rare autosomal recessive disorders: Carnevale, Mingarelli, Malpuech, and Michels syndromes, characterized by variable expression of facial dysmorphia, cleft lip/palate, postnatal growth deficiency, hearing loss, cognitive impairment, craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies. More recently, bi-allelic variants in COLEC10 have been described to be associated with 3MC syndrome. Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell migration. We identified nine individuals from five families of Ashkenazi Jewish descent with homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 and phenotype consistent with 3MC syndrome. Carrier frequency was calculated among 52,278 individuals of Jewish descent. Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%. Molecular protein modeling suggested that the p.Gly104Val substitution alters local conformation. The c.311G > T (p.Gly104Val) variant likely represents a founder variant, and homozygosity is associated with features of 3MC syndrome. 3MC syndrome should be in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and cleft palate.

Post-traumatic radioulnar synostosis: a retrospective case series of 10 patients in Kuwait.

BACKGROUND: The development of radioulnar synostosis due to post-traumatic injuries of the elbow or forearm can lead to debilitating outcomes. Several treatment options are available to hinder the progression and prevent recurrence. We used a combination of these treatments in a series of patients and observed the outcomes. METHODS: We conducted a retrospective study of 10 patients with post-traumatic radioulnar synostosis (9 men and 1 woman) who required surgical intervention in a tertiary orthopedic center. All of these patients were subjected to the same treatment combination (preoperative radiotherapy, tissue interposition after heterotopic ossification resection, and adjuvant indomethacin postoperatively). Improvement in range of motion (flexion, extension, and rotation) and the Mayo score was assessed and compared preoperatively and postoperatively via statistical analysis. RESULTS: In comparison to the patients' preoperative state, which ranged from poor to fair, all 10 patients reported excellent Mayo scores after intervention with the triple therapy combination, with a mean Mayo score of 36 ± 10.2 points. Flexion, extension, and rotation improved by mean values of 55.2° ± 38.7°, 50.2° ± 34.0°, and 47.9° ± 40.0°, respectively. There was 1 complication that has subsided on follow-up. CONCLUSION: The triple therapy combination was found to provide good functional and prophylactic results preventing recurrence.

Double-level Intraperiosteal Derotational Osteotomy for Congenital Radioulnar Synostosis.

BACKGROUND: Many operative methods have been reported for the treatment of congenital radioulnar synostosis (CRUS) and their indications remain controversial. The aim of this study is to evaluate the clinical, radiologic, and functional results of the 2-stage derotational osteotomy with periosteal preservation for CRUS in children. METHODS: From a total of 102 children with CRUS, a retrospective evaluation of 14 consecutive patients (18 forearms) who underwent 2-stage derotational osteotomy of the distal third radius and proximal third ulna with periosteal preservation, bone segment removal, morselization and grafting and cast immobilization was performed. Children with bilateral involvement and/or pronation (>60 degrees), and substantial functional limitations in daily activities were considered candidates for surgery to obtain the desired position of 0 to 20 degrees of pronation. Electronic medical records, preoperative and postoperative clinical and radiologic examinations were reviewed. Also, functional results and parental satisfaction were assessed and statistically analyzed. RESULTS: The median age at the time of surgery was 6.87 (5.02 to 11.22) years. The median follow-up was 38.62 (24.79 to 81.20) months. The median preoperative pronation deformity was 80 (70 to 90) degrees, while the final position was 0 (0 to 10) degrees of pronation ( P <0.01). Elbow flexion and extension showed no changes after surgery. All patients successfully achieved union at 8 (6 to 10) weeks. No complications were observed, and no patient required revision surgeries. The ability to perform daily activities improved markedly, and all patients were satisfied with the results of the surgery. CONCLUSIONS: Two-stage double-level intraperiosteal derotational osteotomy is a safe, simple, and effective procedure in children with CRUS with severe deformity and limitation in performing basic daily living activities. Functional improvement and patient satisfaction are total, and so far no complications have been reported. LEVEL OF EVIDENCE: Level III-treatment study, retrospective comparative study.

Prevalence and risk factors of radial ray deficiencies: A population-based case-control study.

Radial ray deficiency is the most common congenital deficiency of the upper limb. The aim of our study was to investigate maternal risk factors for radial ray deficiencies. We conducted a nationwide population-based case-control study using national registers. All cases with a radial ray deficiency born between 1996 and 2008 were included in the study and compared with five controls without limb deficiency. In total, 115 (10 isolated, 18 with multiple congenital anomalies, and 87 syndromic) cases with radial ray deficiencies were identified and compared with 575 matched controls. The total prevalence in Finland was 1.22 per 10,000 births. No significant risk factors were observed for nonsyndromic cases. In the syndromic group, advanced maternal age (≥35 years) increased the risk of radial aplasia (aOR 2.45, 95% CI 1.37-4.36), and a similar association was observed with multiple pregnancy (aOR 2.97, 1.16-7.62) and male sex (aOR 1.96, 1.18-3.25). Valproic acid was also a risk factor (p = .002). In conclusion, novel associations in the syndromic group of advanced maternal age and multiple pregnancy and increased risk of radial ray deficiencies were observed. Also, early reports on increased risk of RRD associated with valproate and male sex were supported by our results.

Nonlethal presentations of CYP26B1-related skeletal anomalies and multiple synostoses syndrome.

Retinoic acid exposures as well as defects in the retinoic acid-degrading enzyme CYP26B1 have teratogenic effects on both limb and craniofacial skeleton. An initial report of four individuals described a syndrome of fetal and infantile lethality with craniosynostosis and skeletal anomalies caused by homozygous pathogenic missense variants in CYP26B1. In contrast, a 22-year-old female was reported with a homozygous missense pathogenic variant in CYP26B1 with complex multisuture craniosynostosis and intellectual disability, suggesting that in some cases, biallelic pathogenic variants of CYP26B1 may be compatible with life. Here we describe four additional living individuals from two families with compound heterozygous pathogenic missense variants in CYP26B1. Structural assessment of these additional missense variants places them further from the catalytic site and supports a model consistent with milder nonlethal disease. In addition to previously reported findings of multisuture craniosynostosis, conductive hearing loss, joint contractures, long slender fingers, camptodactly, broad fingertips, and developmental delay/intellectual disability, skeletal imaging in our cases also revealed gracile long bones, gracile ribs, radioulnar synostosis, and carpal and/or tarsal fusions. These individuals broaden the phenotypic range of biallelic pathogenic variants in CYPB26B1 and most significantly clarify that mortality can range from perinatal lethality to survival into adulthood.

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 case series review of patients with Thrombocytopenia and Absent-Radii syndrome (TARS) and their management during pregnancy.

Bleeding diatheses due to platelet-related disorders can present challenges to treating clinicians, especially in the context of peri- and post-partum patients in the obstetric setting. Thrombocytopenia and Absent-Radii syndrome (TARS) is an inherited disorder characterized by reduced bone marrow platelet production, skeletal deformities affecting radii and other limbs; cardiac, renal, and other heterogeneous anomalies may occur. It is caused by the co-inheritance of a microdeletion and a nucleotide polymorphism in the RBM8A gene on chromosome 1. Bleeding phenotype is more severe than platelet numbers which might predict especially in infants but improves with age. There is minimal literature regarding the impact of pregnancy and puerperium. We describe the management of three pregnancies in the hematology-obstetrics clinic. As platelet counts normally decrease through pregnancy, close monitoring is required in TARS. No major bleeding was seen antenatally but two required platelet transfusions during labor. No other treatment definitely improves bleeding, although case reports of steroids claim variable success. Tranexamic acid may be helpful, and thrombopoietin agonists represent a potential future option.

Application of 3-Dimensional Printing Technology in Rotational Osteotomy of Congenital Radioulnar Synostosis.

PURPOSE: To investigate whether computer-aided design (CAD) and 3-dimensional printing technology can assist in accurate completion of ulna-radius proximal rotational osteotomy in congenital radioulnar synostosis (CRUS). METHODS: We treated 1 right arm and 4 left arms of 4 boys with a mean age of 5.2 years (range, 4.3-6.0 years) between July 2018 and April 2019. Computed tomography (CT) scans of the forearm were performed on the children before surgery. Using the CT data, the pronation angle of the forearm was measured. An individualized dial with a matching forearm diameter was designed before surgery to control the angle of the rotational osteotomy. Ulna and radius models, and individualized dials, were prepared for each patient using 3-dimensional printing technology. Preoperative simulated surgery was performed using the 3-dimensional printed models. During the surgery, 2 Kirschner wires were used as operating levers for rotation, and rotational angle correction was precisely controlled using the dial. The cast and internal fixation were removed after x-ray examination showed that the osteotomy had healed, about 5 weeks after surgery. RESULTS: The rotational osteotomies were completed in a single operation, and the correction angle was 60°. No complications occurred after the operation. All patients showed functional improvements in activities of daily living. CONCLUSIONS: For CRUS patients, models and dials made with CAD and 3-dimensional printing technology can assist in precise rotational osteotomy. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Roberts syndrome in an Indian patient with humeroradial synostosis, congenital elbow contractures and a novel homozygous splice variant in ESCO2.

Roberts syndrome (also known as Roberts-SC phocomelia syndrome) is an autosomal recessive developmental disorder, characterized by pre- and postnatal growth retardation, limb malformations including bilateral symmetric tetraphocomelia or mesomelia, and craniofacial dysmorphism. Biallelic loss-of-function variants in ESCO2, which codes for establishment of sister chromatid cohesion N-acetyltransferase 2, cause Roberts syndrome. Phenotypic spectrum among patients is broad, challenging clinical diagnosis in mildly affected individuals. Here we report a 3-year-old boy with a mild phenotype of Roberts syndrome with bilateral elbow contractures, humeroradial synostosis, mild lower limb disparity, and facial dysmorphism. Trio whole-exome sequencing identified the novel biallelic splice variant c.1673+1G>A in ESCO2 in the patient. Aberrant ESCO2 pre-mRNA splicing, reduced relative ESCO2 mRNA amount, and characteristic cytogenetic defects, such as premature centromere separation, heterochromatin repulsion, and chromosome breaks, in patient cells strongly supported pathogenicity of the ESCO2 variant affecting one of the highly conserved guanine-thymine dinucleotide of the donor splice site. Our case highlights the difficulty in establishing a clinical diagnosis in individuals with minor clinical features of Roberts syndrome and normal intellectual and social development. However, next-generation sequencing tools allow for molecular diagnosis in cases presenting with mild developmental defects.