Raine syndrome: Prenatally identified severe craniofacial phenotype with multisuture synostosis and brain abnormalities associated with variants in FAM20C.

Raine syndrome (MIM 259775) is a rare autosomal recessive disorder, first described by Raine et al. in 1989, with an estimated prevalence of <1/1,000,000. This is due to pathogenic variants in FAM20C characterized by osteosclerosis, typical craniofacial features, and brain calcifications. Here, we report a novel variant in FAM20C, describe a uniquely severe craniofacial and CNS phenotype of Raine syndrome, and correlate it with prenatal findings. Fetal phenotyping was based on ultrasound and MRI. Solo exome sequencing was performed from DNA extracted from postmortem skin biopsy. Targeted parental variant testing was subsequently performed. A homozygous missense variant NM_020223.4 (c.1445 G > A (p.Gly482Glu)) was identified in FAM20C associated with Raine syndrome. The infant had the characteristic dysmorphic features seen in Raine syndrome. He had particularly significant CNS manifestations consisting of multisuture craniosynostosis with protrusion of the brain parenchyma through fontanelles and cranial lacunae. Histological sections of the brain showed marked periventricular gliosis with regions of infarction, hemorrhage, and cavitation with global periventricular leukomalacia. Numerous dystrophic calcifications were diffusely present. Here, we demonstrate the identification of a novel variant in FAM20C in an infant with the characteristic features seen in Raine syndrome. The patient expands the characteristic phenotype of Raine syndrome to include a uniquely severe CNS phenotype, first identified on prenatal imaging.

Outcomes of surgical management for tarsal coalitions: a systematic review.

PURPOSE: To analyze the outcome of surgical treatment of tarsal coalition, assess the role of the surgical technique, as well as of coalition size and type on outcomes. METHODS: The search followed the Preferred Reporting Items of Systematic Review and Meta-Analysis and was performed in four databases: MEDLINE, Central, Scopus and Web of Science. The protocol has been registered in the international prospective register of systematic reviews. Patient-reported outcomes (PROMs), complications, revisions and radiographic recurrence were collected. Risk of bias was assessed using MINORS criteria. A random-effects model for meta-analysis was applied for analysis of data heterogeneity. RESULTS: Twenty-five studies including 760 tarsal coalitions were included and had a weighted average follow-up of 44 months. Studies scored fair to poor on the risk of bias assessment with a mean MINORS score of 67% (44-81%). In 77.8% (37.5-100%) of surgically treated tarsal coalitions, good/excellent/non-limiting or improved PROMs were reported. Calculated data heterogeneity was moderate (I2 = 57%). Open bar resection with material interposition had a clinical success rate of 78.8% (50-100%). Complications occurred in 4.96% of cases. Coalition size did not prove to be a determining factor in postoperative outcome. The influence of the coalition type was not investigated by any of the studies. CONCLUSION: Data on outcomes of surgical management for tarsal coalitions is limited to retrospective case series with high risk of bias and moderate data heterogeneity. In about ¾ of cases, open resection and interposition of material results in improved PROMs. The arbitrary margin of ≥ 50% of TC coalition size in relation to the posterior facet has little importance in surgical decision-making. None of the studies reported on the influence of the coalition type on postoperative clinical success.

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 radioulnar synostosis: is prenatal diagnosis possible? - A case report.

OBJECTIVES: The main objectives of this case report are to discuss prenatal ultrasound findings of congenital radioulnar synostosis and to review the literature. CASE REPORT: A patient was diagnosed with congenital radioulnar synostosis at eight months old when parents noticed limited motions in the child's left forearm. The parent denied any traumatic or family history of bony malformations. Physical examination by a pediatric orthopedics specialist and digital radiography revealed proximal radioulnar synostosis. The case report includes perinatal course, comparison between the postnatal radiography and fetal ultrasound images. CONCLUSION: Congenital radioulnar synostosis is often associated with sex chromosome abnormalities and congenital musculoskeletal disorders or syndromes affecting limbs. Isolated congenital radioulnar synostosis is hardly diagnosed before birth, in some cases even have been neglected postnatally. Knowing the developmental milestones of the forearm and specified high-risk groups might help develop a targeted screening strategy to increase the possibility of early detection and intervention.

Resection of Posttraumatic Rib Synostoses Resolves Pulmonary Insufficiency: A Case Report.

CASE: A 30-year-old woman underwent open reduction and internal fixation for multiple segmental rib fractures status post a motor vehicle collision. A year later, the patient presented with extensive intercostal heterotopic ossification associated with multilevel, hemithoracic, rib synostoses compromising her ventilation. The patient subsequently underwent synostoses excision and hardware removal. Pulmonary function tests (PFT), imaging, and patient-reported outcome scores demonstrate resolution of impairment. CONCLUSION: Resection of multilevel, intercostal, rib synostoses provided an effective treatment for pulmonary restrictive disorder secondary to traumatic rib synostosis. This is the first patient with documentation of prereconstructive and postreconstructive PFTs for chest wall synostosis excision.

Thoracic Outlet Syndrome with Subclavian Artery Thrombosis Caused by Synostosis of the First and Second Ribs: A Case Report.

CASE: A 43-year-old woman presented with pain, paresthesia, and coldness of the right upper extremity suggestive of the diagnosis of thoracic outlet syndrome. Three-dimensional computed tomography angiography revealed that the right subclavian artery was constricted because it traveled over an abnormal first rib. After anticoagulation and antithrombotic therapy, the patient underwent resection of the abnormal first rib. Postoperative angiography documented improvement over time of the poststenotic dilatation and recanalization of the subclavian artery capable of delivering almost normal distal flow. CONCLUSION: Arterial reconstruction is not always necessary for the treatment of arterial thoracic outlet syndrome associated with poststenotic dilatation of the subclavian artery.

Post-traumatic Radioulnar Synostosis in Distal Forearm Fractures in Children: A Report of 2 Cases.

CASES: Two pediatric cases of post-traumatic distal radioulnar synostosis are reported, accompanied by a literature review summarizing evidence on the management of these conditions. Radioulnar synostosis is a rare complication of distal forearm fractures, which impairs upper-extremity function. The numerous surgical procedures that have been described to treat this condition in adults typically involve synostosis resection and an interposition graft to reduce recurrence. The optimal treatment in children has not been established. CONCLUSIONS: Post-traumatic radioulnar synostoses are rare conditions in pediatric patients who can be successfully treated with surgical excision of the synostoses and without the use of interposition grafting.

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.

Identifying the Misshapen Head: Craniosynostosis and Related Disorders.

Pediatric care providers, pediatricians, pediatric subspecialty physicians, and other health care providers should be able to recognize children with abnormal head shapes that occur as a result of both synostotic and deformational processes. The purpose of this clinical report is to review the characteristic head shape changes, as well as secondary craniofacial characteristics, that occur in the setting of the various primary craniosynostoses and deformations. As an introduction, the physiology and genetics of skull growth as well as the pathophysiology underlying craniosynostosis are reviewed. This is followed by a description of each type of primary craniosynostosis (metopic, unicoronal, bicoronal, sagittal, lambdoid, and frontosphenoidal) and their resultant head shape changes, with an emphasis on differentiating conditions that require surgical correction from those (bathrocephaly, deformational plagiocephaly/brachycephaly, and neonatal intensive care unit-associated skill deformation, known as NICUcephaly) that do not. The report ends with a brief discussion of microcephaly as it relates to craniosynostosis as well as fontanelle closure. The intent is to improve pediatric care providers' recognition and timely referral for craniosynostosis and their differentiation of synostotic from deformational and other nonoperative head shape changes.

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.

Intradiploic Hematoma Associated With Synostosis in an Infant.

Intradiploic hematomas are extremely rare, particularly in newborns. Caused by bleeding between the inner and outer tables of the calvarium, they manifest with bony swelling of the skull. The authors present the first case of an intraosseous hematoma associated with synostosis, and the first report in a female patient. The clinical, radiological, surgical, and pathological characteristics of this lesion are discussed.

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.

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.

Ulnar osteotomy and the ilizarov mini-fixator for pediatric chronic monteggia fracture-dislocations.

Treatment of chronic Monteggia fracture-dislocations remains controversial in skeletally immature patients. The present study aimed to review the clinical outcomes of surgical treatment with an Ilizarov mini-fixator for chronic Monteggia fracture-dislocations in children. From April 2003 to March 2014, 5 pediatric patients (4 males, 1 female) with chronic Monteggia fracture-dislocation were treated with an Ilizarov mini-fixator at our institution. The median age at the time of surgery was 9 years (range 5-14 years), median duration from injury to surgery was 31 months (range 2-125 months), and median duration of follow-up was 12 months (range 11 months-10 years). All patients underwent opening wedge osteotomy of the proximal ulna followed by the application of an Ilizarov mini-fixator. Although closed reduction was attempted after ulnar osteotomy and application of the Ilizarov mini-fixator, open reduction of the radial head was required in all patients. In 4 patients, dense scar tissue in the radiocapitellar joint was excised to enable reduction of the radial head; the remaining patient had traumatic radioulnar synostosis, and underwent separation of the synostosis followed by anconeus interposition arthroplasty. No patient received bone grafting at the ulnar osteotomy site, repair or reconstruction of the annular ligament, or temporary fixation of the radial head with transarticular wire. The median period of external fixation was 10 weeks (range 8-13 weeks). Although there were no severe complications such as deep infection and neurovascular disturbance, asymptomatic radial head subluxation occurred in 2 patients. The patient with traumatic synostosis had residual posterior subluxation with limitation of forearm rotation, and another patient with radial head enlargement had residual anterior subluxation. The median postoperative ranges of motion in pronation, supination, extension, and flexion were 90°, 90°, 0°, and 140°, respectively. The median Kim's elbow performance score was 65 (range 50-75) preoperatively, which improved to 94 (range 80-100) at final follow-up. The outcome was rated as excellent in 4 cases, and good in 1. In pediatric chronic Monteggia fracture-dislocations, ulnar osteotomy followed by the application of an Ilizarov mini-fixator is a viable option that is less invasive than plate fixation.

Synostosis of the first and second ribs in six horses.

CASE DESCRIPTION Over a 2-year period, 6 horses (4 Selle Français, 1 Hanoverian, and 1 Thoroughbred) were referred for evaluation of forelimb lameness. All horses had radiographic evidence of synostosis of the first and second ribs (SFSR). CLINICAL FINDINGS For 1 horse, the SFSR was considered the probable cause of the lameness (grade 3/5), with a shortening of the cranial phase of the stride in the affected limb. For 3 horses, it was considered a possible cause of the lameness (grade 1/5) for the same reason. For 2 horses, SFSR was considered an incidental finding unassociated with any clinical signs. The 4 horses with lameness suspected as attributable to SFSR had a moderate to severe amount of irregularly marginated new bone formation at the site of the SFSR, with a cranial displacement of the first rib, compared with findings for the 2 horses in which the SFSR was considered incidental. A likely congenital abnormality of the first rib was first suspected on nuclear scintigraphy in the 1 horse for which it was performed or on radiography of the caudal cervical portion of the vertebral column (3 horses) or shoulder joint (2 horses). TREATMENT AND OUTCOME The horse in which SFSR was considered the probable cause of the lameness was retired to the field and remained chronically lame. Two of the 3 horses in which SFSR was considered a possible cause of lameness received an IV infusion of tiludronate disodium and mesotherapy over the caudal cervical and cranial thoracic regions; both returned to competition but with poor results. One of the 2 horses with subclinical SFSR never developed lameness on the affected side. No follow-up information was available for the other 2 horses. CLINICAL RELEVANCE SFSR can be an incidental finding in horses, with or without clinical manifestations. This abnormality should be considered as a differential diagnosis for horses with forelimb lameness and associated shortening of the cranial phase of the stride that fails to improve with diagnostic analgesic techniques.

Bilateral congenital dislocation of the patella associated with synostosis of proximal tibiofibular and proximal radioulnar joints: A case report.

Congenital dislocation of the patella is a rare and difficult pathology to treat. We present a case of bilateral congenital dislocation of the patella with synostosis of proximal tibiofibular and proximal radioulnar joints without genu valgum deformity of both knees in a 30-year-old man. To our knowledge, congenital dislocation of the patella associated with synostosis of proximal tibiofibular and proximal radioulnar joints has not been reported in the literature yet.

Sinostosis cervical asociada a síndromes de Down y de Schneider. Implicaciones clínicas y médico-legales a propósito de un caso autópsico / Cervical synostosis associated with Down's syndrome and Schneider syndrome. Clinical and medico-legal implications of an autopsy case

Con ocasión de un caso de asociación entre síndrome de Down y sinostosis vertebral congénita que sufrió lesión medular traumática, se revisa la asociación de estos cuadros y sus implicaciones clínicas y forenses. La literatura no ha comunicado hasta ahora una asociación prevalente entre síndrome de Down y sinostosis cervicales. Ambos cuadros por separado propenden a la mielopatía cervical, bien de manera degenerativa, bien traumática. En consecuencia, la asociación de ambos debe verse como un factor de riesgo de daño medular o de manera espontánea o, sobre todo, después de traumatismos. En estos casos, la exploración radiológica debe ser exhaustiva incluyendo RMN ya que pueden existir lesiones medulares incluso ante traumatismos mínimos. En caso de fallecimiento, la autopsia medular es obligada ya que puede revelar lesiones subclínicas, clarificar la naturaleza y extensión de las lesiones medulares y esqueléticas, así como ayudar a establecer una mejor correlación anatomoclínica

This paper reviews the association of clinical symptoms and their clinical and forensic implications in a patient with Down's syndrome and congenital cervical synostosis who experienced a traumatic spinal cord injury. To date, no prevalent association between Down's syndrome and cervical synostosis has been reported in the literature. Given that both entities are prone to cause degenerative or traumatic cervical myelopathy, the combination of both conditions must be seen as a risk factor for spontaneous, and particularly traumatic, spinal cord damage. In these cases, radiological examination must be exhaustive, including MRI, given the possibility of spinal cord injury even after minimal trauma. In the event of death, spinal cord autopsy is mandatory as it may reveal subclinical lesions, clarify the nature and extension of the spinal cord and skeletal injuries and help to establish an improved anatomo-clinical correlation