Assessment of copy number variations in 120 patients with Poland syndrome.

BACKGROUND: Poland Syndrome (PS) is a rare congenital disorder presenting with agenesis/hypoplasia of the pectoralis major muscle variably associated with thoracic and/or upper limb anomalies. Most cases are sporadic, but familial recurrence, with different inheritance patterns, has been observed. The genetic etiology of PS remains unknown. Karyotyping and array-comparative genomic hybridization (CGH) analyses can identify genomic imbalances that can clarify the genetic etiology of congenital and neurodevelopmental disorders. We previously reported a chromosome 11 deletion in twin girls with pectoralis muscle hypoplasia and skeletal anomalies, and a chromosome six deletion in a patient presenting a complex phenotype that included pectoralis muscle hypoplasia. However, the contribution of genomic imbalances to PS remains largely unknown. METHODS: To investigate the prevalence of chromosomal imbalances in PS, standard cytogenetic and array-CGH analyses were performed in 120 PS patients. RESULTS: Following the application of stringent filter criteria, 14 rare copy number variations (CNVs) were identified in 14 PS patients in different regions outside known common copy number variations: seven genomic duplications and seven genomic deletions, enclosing the two previously reported PS associated chromosomal deletions. These CNVs ranged from 0.04 to 4.71 Mb in size. Bioinformatic analysis of array-CGH data indicated gene enrichment in pathways involved in cell-cell adhesion, DNA binding and apoptosis processes. The analysis also provided a number of candidate genes possibly causing the developmental defects observed in PS patients, among others REV3L, a gene coding for an error-prone DNA polymerase previously associated with Möbius Syndrome with variable phenotypes including pectoralis muscle agenesis. CONCLUSIONS: A number of rare CNVs were identified in PS patients, and these involve genes that represent candidates for further evaluation. Rare inherited CNVs may contribute to, or represent risk factors of PS in a multifactorial mode of inheritance.

Subclinical myopathy in a child with neutral lipid storage disease and mutations in the PNPLA2 gene.

We report a 14-year-old-boy with markedly elevated serum creatine kinase (CK) levels, in whom massive triglyceride storage was found in peripheral blood leukocytes and in muscle biopsy. Sequencing PNPLA2, the gene encoding the adipose triglyceride lipase (ATGL) and responsible for the neutral lipid storage disease with myopathy (NLSDM), we identified two heterozygous mutations, including a previously reported nonsense and a novel missense mutation in the patatin domain of the gene. Lipid storage myopathy can be clinically silent in childhood and presenting only with hyperCKemia.

Familial Poland anomaly revisited.

Poland anomaly (PA) is a pectoral muscle hypoplasia/aplasia variably associated with ipsilateral thoracic (TA) and/or upper limb anomalies (ULA). PA is usually sporadic and sometimes familial, making recurrence risk an issue in genetic counseling. Multidisciplinary evaluation of 240 PA patients was carried out, including physical examination of patients and their parents in 190 PA (subjects of the study). Familial conditions were classified into three groups. Group1: true familial PA (F-PA): pectoral muscle defects with familial recurrence: 8(4.2%). Group2: familial Poland-like anomaly families (F-PLA): PA index case and ≥1 relative(s) showing normal pectoral muscles but ULA and/or TA common in PA: 16(8.4%). Group3: sporadic PA (S-PA): 166(87.4%). F-PA indicated a stronger male (87.5%) and left side (62.5%) prevalence, but fewer ULA (37.5%) compared to the other two groups. Maternal transmission (6/8) was more common in F-PA. Statistical significance was not reached due to the small number of F-PA and F-PLA. Karyotyping and array-comparative genomic hybridization were performed in 13 families. Three maternally inherited copy number variants were identified in three patients: 1p31.1 deletion, Xp11.22 duplication, and 16q23.1 duplication. Interestingly, the proband's mother carrying the 16q23.1 duplication displayed moderate breast and areola asymmetry, but normal pectoral muscles on ultrasound. Though there is no recent review discussing recurrence of PA, we reviewed 31 published PA families. On the basis of our study and previous reports, familial PA is not uncommon. Nonetheless, no information can be derived either regarding a molecular basis or clinical tools with which to identify cases with recurrence risk.

Development and preliminary validation of a paediatric-targeted MRI scoring system for the assessment of disease activity and damage in juvenile idiopathic arthritis.

OBJECTIVES: To develop and validate a paediatric-targeted MRI scoring system for the assessment of disease activity and damage in juvenile idiopathic arthritis (JIA). To compare the paediatric MRI score with the adult-designed. Outcome Measures in Rheumatology Clinical Trials-Rheumatoid Arthritis MRI Score (RAMRIS), whose suitability for assessing growing joints was tested. METHODS: In 66 patients with JIA the clinically more affected wrist was studied. Thirty-nine patients had a 1-year MRI follow-up. Two readers independently assigned the paediatric score and the RAMRIS to all studies. Validation procedures included analysis of reliability, construct validity and responsiveness to change. A reduced version of the bone erosion score was also developed and tested. RESULTS: The paediatric score showed an excellent reproducibility (interclass correlation coefficient >0.9). The interobserver agreement of RAMRIS was moderate for bone erosions and excellent for bone marrow oedema (BMO). The paediatric score and RAMRIS provided similar results for construct validity. The responsiveness to change of the paediatric score was moderate for synovitis and bone erosion, and poor for BMO and did not improve when RAMRIS was applied. The reduced version of the bone erosion was valuable for the assessment of joint damage, and provided time-saving advantages. CONCLUSION: The results demonstrate that the paediatric MRI score is a reliable and valid method for assessing disease activity and damage in JIA. Unexpectedly, the RAMRIS provides acceptable suitability for use in the paediatric age group. Further work, especially in a longitudinal setting, is required before defining the most suitable MRI scale for assessing growing joints.

Paediatric musculoskeletal US beyond the hip joint.

US is a technique particularly suited to the investigation of musculoskeletal disorders in children and adolescents. This review paper describes a range of clinical settings beyond the hip joint where US has a significant role to play, including sports injuries, infectious diseases, inflammatory and degenerative conditions, congenital and developmental disorders, acute trauma of bone and joints, and peripheral nerve injuries. In some circumstances, US can be regarded as the most effective means of diagnostic imaging, whereas in other instances, it is an alternative or supplement to other more comprehensive imaging modalities, like MRI and CT. Although MRI offers superior soft-tissue contrast resolution, US is low-cost, non-invasive and has higher spatial resolution and real-time capability for the assessment of musculoskeletal structures during joint movement and stress manoeuvres.

Muscle variants of the upper and lower limb (with anatomical correlation).

Several accessory muscles in the upper and lower limb have been described in the medical literature. Most are asymptomatic and represent incidental findings at imaging. In some instances, however, these muscles may become clinically relevant producing palpable swelling, entrapment of neurovascular structures, or exercise-related pain. The diagnosis of accessory muscles is based on recognition of their typical location and on cross-sectional imaging features. Familiarity with their most common location and knowledge of the possible clinical syndromes caused by these supernumerary structures may aid in diagnosis and treatment.

Imaging of neuropathies about the ankle and foot.

Neuropathies about the ankle and foot may be the cause of chronic pain and disability. In most cases, these conditions derive from mechanical or dynamic compression of a segment of a nerve within a narrow osteofibrous tunnel, an opening in a fibrous structure, or a passageway close to a ligament or a muscle. Although the evaluation of nerve disorders primarily relies on neurological examination and electrophysiology, diagnostic imaging is currently used as a complement to help define the site and etiology of nerve compression and exclude other disease possibly underlying the patient' symptoms. In this article, a review of the anatomical and pathological features of nerve entrapments in the distal lower extremity is presented on ultrasound and magnetic resonance imaging, according to the nerve involved.

Consensus based recommendations for diagnosis and medical management of Poland syndrome (sequence).

BACKGROUND: Poland syndrome (OMIM: 173800) is a disorder in which affected individuals are born with missing or underdeveloped muscles on one side of the body, resulting in abnormalities that can affect the chest, breast, shoulder, arm, and hand. The extent and severity of the abnormalities vary among affected individuals. MAIN BODY: The aim of this work is to provide recommendations for the diagnosis and management of people affected by Poland syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years affected subjects. The literature search was performed in the second half of 2019. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus. CONCLUSION: Being Poland syndrome a rare syndrome most recommendations here presented are good clinical practice based on the consensus of the participant experts.

Poland syndrome with bilateral features: case description with review of the literature.

Poland syndrome (PS) has been described as unilateral pectoral muscle deficiency variably associated with ipsilateral thoracic and upper limb anomalies. Bilateral hypoplasia/aplasia of the pectoralis muscle and upper limb defects in association with variable thoracic muscles, chest wall deformities and lower limb defects have been infrequently reported in the literature. We report on a 3(1/2)-year-old girl with clinical features consisting in bilateral asymmetric pectoral muscle defects (complete agenesis on the left side and agenesis of the sternocostal head on the right side), nipple hypoplasia, left rib defect, and right hand symbrachydactyly. In this study, we reviewed the bilateral features present in our patient and those described in the literature. Hypotheses explaining bilateral features in PS are reviewed.

Poland syndrome: A proposed classification system and perspectives on diagnosis and treatment.

Poland Syndrome (PS) is a rare condition, with an estimated incidence of approximately 1 per 30,000 births and encompasses a wide range of severities of chest and upper arm anomalies. The etiology remains unknown, but genetic involvement is suspected. Few radiological investigations have proven useful in the study PS phenotypes and we propose a reference algorithm for guiding pediatricians. Our experience with 245 PS patients in the last 10 years stimulated a phenotypical classification of PS. The management of the different PS types and a therapeutic algorithm according to the phenotypical features of each PS patient are also proposed.

Intraneural Ganglia of the Common Peroneal Nerve in Children: Case Report and Review of the Literature.

OBJECTIVES: Intraneural ganglia are nonneoplastic cystic formations contained within the epineurium of peripheral nerves. The common peroneal nerve at the fibular neck is the most frequently affected site. Intraneural ganglia are not a frequent occurrence in the adult patients and are even rarer in children, with only 10 pediatric cases reported in the English language literature. We report on a new pediatric case of intraneural ganglion of common peroneal nerve and present a review of the English language literature on this topic in children. METHODS: A 10-year-old girl was admitted to our institution because of pain referred to posterior and anterior aspects of the right leg and right foot drop. The radiologic investigations showed a wide (20 cm long) intraneural ganglion cyst of the right common peroneal nerve. The patient underwent surgical treatment according to the Spinner technique. RESULTS: Postoperative course was uneventful. A gradual improvement of motor and sensory functions was observed, starting from the third postoperative day, with a complete motor function restoration registered 26 months after surgery. CONCLUSIONS: Intraneural ganglia of the common peroneal nerve should always be considered in the differential diagnosis of foot drop in pediatric age since because early diagnosis and adequate surgical treatment play a crucial role in the patient's motor and sensory outcomes.

Proposal of the TBN Classification of Thoracic Anomalies and Treatment Algorithm for Poland Syndrome.

BACKGROUND: Poland syndrome is a congenital deformity characterized by unilateral anomalies of pectoralis muscles, breast, nipple, axillary fold, subcutaneous tissue, ribs, and upper limb. The thoracic anomaly, which is the pathognomonic malformation of Poland syndrome, presents a wide phenotype variability and has been classified by different authors. However, these classifications do not include all the possible phenotypes of Poland syndrome. The aim of this study is to propose a simple classification of the whole spectrum of thoracic anomalies and a treatment algorithm that could have a practical value for determining the surgical approach. METHODS: Since 2008, 100 patients have been evaluated by the same plastic surgical team at San Martino Hospital-IST and Istituto Gaslini of Genoa, Italy, using the thorax, breast, nipple-areola complex (TBN) classification. Thoracic anomalies were classified as follows: thorax (T), from T1 (muscle defect only) to T4 (complex deformity with rib and sternal involvement); breast (B), in B1 (hypoplasia) or B2 (amastia); and nipple-areola complex (N), from N1 (dislocation <2 cm) to N3 (athelia). RESULTS: The most frequent thoracic anomalies were T1 (47 percent) and N2 (74 percent), whereas in female patients, B1 was more frequent than B2. The surgical approach to breast and pectoral reconstruction was based not only on the patient's age and sex, but also on the type of anomaly according to the TBN classification. In particular, a two-step approach with tissue expanders was required in N2 and N3 cases, whereas in N1 patients a single step was sufficient. CONCLUSION: The TBN classification can be a useful tool for surgical decision-making according to each specific thoracic anomaly. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV.

Agreement among musculoskeletal pediatric specialists in the assessment of radiographic joint damage in juvenile idiopathic arthritis.

OBJECTIVE: To evaluate agreement among musculoskeletal pediatric specialists in assessing radiographic joint damage in juvenile idiopathic arthritis (JIA). METHODS: Two pediatric rheumatologists, 2 pediatric radiologists, and 2 pediatric orthopedic surgeons evaluated independently 60 radiographs of both wrists and hands of children with polyarticular-course JIA. Films were scored using an adapted and simplified version of the Larsen score, ranging from 0-5. Study radiographs were selected from 568 films used in a previous study aimed to validate an adapted pediatric version of the Sharp/van der Heijde (SHS) score. To enable comparison of specialists' scores with the adapted SHS score, the 60 radiographs were divided into 6 classes of severity of damage based on quintiles of the adapted SHS score. Agreement was evaluated in terms of absolute agreement and through weighted kappa statistics. RESULTS: The pediatric radiologists tended to assign lower scores and to provide more frequently scores of 0 than did the other specialists. Weighted kappa for the 3 pairs of specialists ranged from 0.67-0.69, indicating substantial agreement. Absolute agreement ranged from 51.3-55.7%, depending on the pair of specialists examined. Both absolute and weighted kappa concordance between specialists' scores and the adapted SHS score were poorer for the pediatric radiologist than for the other specialists. CONCLUSION: We observed fair agreement in the assessment of radiographic damage among pediatric specialists involved in the care of children with JIA. The radiologists tended to be more reserved than the rheumatologists and orthopedic surgeons in labeling radiographs as damaged or in considering changes as important.

Hip ultrasound.

In newborns, US has an established role in the detection and management of developmental dysplasia of the hip. Later in childhood, when the limping child is a major diagnostic dilemma, US is extremely helpful in the identification of the varied disease processes underlying this condition, as transient synovitis, septic arthritis, Perthes disease and slipped femoral capital epiphysis. In adolescent practicing sporting activities, US is an excellent means to identify apophyseal injures about the pelvic ring, especially when avulsions are undisplaced and difficult-to-see radiographically. Later on, in the adulthood, US is an effective modality to diagnose tendon and muscle injuries about the hip and pelvis, identify effusion or synovitis within the hip joint or its adjacent bursae and guide the treatment of these findings. The aim of this article is to provide a comprehensive review of the most common pathologic conditions about the hip, in which the contribution of US is relevant for the diagnostic work-up.

Dextrocardia in patients with Poland syndrome: phenotypic characterization provides insight into the pathogenesis.

OBJECTIVE: Poland syndrome is a rare congenital anomaly characterized by complete or partial agenesis of the pectoralis major muscle variably associated with other thoracic malformations, upper limb malformations, or both. More than 20 patients with dextrocardia and left-sided Poland syndrome have been previously described. The association between these 2 rare anomalies suggests a causal relationship, but the etiopathogenetic mechanism has not been clarified yet. We studied the clinical correlation between these 2 anomalies, and we tried to elucidate whether dextrocardia or Poland syndrome comes first. METHODS: This is a multicentric multidisciplinary study conducted over the last 5 years. We identified 122 patients with Poland syndrome, and we investigated heart position through different imaging techniques. Logistic regression statistical analyses were carried out. RESULTS: We observed dextrocardia in 14 (11.5%) patients, which was never associated with situs inversus. All of them presented with left-sided Poland syndrome and partial agenesis of 2 or more ribs. Conversely, all patients with Poland syndrome with partial agenesis of 2 or more ribs presented with dextrocardia, whereas dextrocardia was never associated with partial agenesis of a single rib. Three patients with dextrocardia presented with simple congenital heart defects. CONCLUSIONS: These findings suggest that mechanical factors during embryonic life could explain the strong association between left-sided Poland syndrome and dextrocardia. According to this hypothesis, partial agenesis of 2 or more ribs is needed to displace the heart toward the right side. The peculiar features of dextrocardia when associated with Poland syndrome (neither associated with situs inversus nor complex intracardiac anomalies) support our hypothesis.

Development and initial validation of a radiographic scoring system for the hip in juvenile idiopathic arthritis.

OBJECTIVE: To develop and validate a radiographic scoring system for the assessment of radiographic damage in the hip joint in patients with juvenile idiopathic arthritis (JIA). METHODS: The Childhood Arthritis Radiographic Score of the Hip (CARSH) assesses and scores these radiographic abnormalities: joint space narrowing (JSN), erosion, growth abnormalities, subchondral cysts, malalignment, sclerosis of the acetabulum, and avascular necrosis of the femoral head. Score validation was accomplished by evaluating reliability and correlational, construct, and predictive validity in 148 JIA patients with hip disease who had a total of 381 hip radiographs available for study. RESULTS: JSN was the most frequently observed radiographic abnormality, followed by erosion and sclerosis of the acetabulum. The least common abnormalities were avascular necrosis, growth abnormalities, and malalignment. Interobserver and intraobserver reliability on baseline and longitudinal score values and on score changes was good, with intraclass correlation coefficients ranging from 0.76 to 0.98. Early score changes, but not absolute baseline score values, were moderately correlated (r(s) > 0.4) with clinical indicators of disease damage at last followup observation, thereby demonstrating that the CARSH has good construct and predictive validity. The amount of structural damage in the hip radiograph at last followup observation was predicted better by baseline to 1-year score change (r(s) = 0.66; p < 0.0001) than by absolute baseline score values (r(s) = 0.40; p = 0.002). CONCLUSION: Our results show that the CARSH is reliable and valid for the assessment of radiographic hip damage and its progression in patients with JIA.

Magnetic resonance imaging, ultrasonography, and conventional radiography in the assessment of bone erosions in juvenile idiopathic arthritis.

OBJECTIVE: To compare magnetic resonance imaging (MRI), conventional radiography, and ultrasonography in identifying bone erosions in patients with juvenile idiopathic arthritis (JIA), and to determine the validity and reliability of an MRI scale in detecting and grading joint damage. METHODS: In 26 JIA patients, the clinically more affected wrist was studied with MRI, radiography, and ultrasonography, coupled with standard clinical assessment and biochemical analysis. MR images were assessed independently by 2 readers according to an apposite devised scoring system. RESULTS: Of 26 patients, 25 (96.1%) had 1 or more erosions as detected by MRI, whereas conventional radiography and ultrasonography revealed erosions in 13 (50%) of 26 and 12 (50%) of 24 patients, respectively. The ability of MRI to detect erosive changes was significantly higher with respect to conventional radiography (P = 0.002 with Bonferroni correction [P(B)]) and ultrasonography (P(B) = 0.0002) in the group of patients with <3 years' disease duration. Ultrasonography and conventional radiography were of equivalent value for the detection of destructive changes. Wrist MRI score correlated highly with radiographic erosion score (r(s) = 0.82) and with wrist limited range of motion score (r(s) = 0.69). The interreader intraclass correlation coefficient (ICC) for MRI score was excellent (0.97); intrareader ICCs were good for both investigators (0.97 and 0.79). CONCLUSION: MRI seems to be a powerful tool to detect early structural damage in JIA. The proposed MRI scale for bone erosions appears promising in terms of reliability and construct validity. The pathophysiologic meaning and the prognostic value of bone erosions revealed only by MRI remain to be established in longitudinal studies.

Use of the Sharp and Larsen scoring methods in the assessment of radiographic progression in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the applicability of the Sharp and Larsen scoring methods for radiographic damage in juvenile idiopathic arthritis (JIA). METHODS: Wrist/hand radiographs of 25 patients with polyarthritis obtained at first observation and then yearly for 4-5 years were assessed independently by 2 pediatric rheumatologists according to the Sharp and Larsen methods. To facilitate score assignment, each patient radiograph was compared with a bone age-related standard. A third pediatric rheumatologist measured the Poznanski score, and a pediatric radiologist provided a semiquantitative assessment of radiographic damage severity. RESULTS: Interobserver and intraobserver agreement on longitudinal scores were good for both Sharp and Larsen methods, with intraclass correlation coefficient >0.9. Agreement on change assessment was good for the Sharp method and moderate for the Larsen method. Both methods yielded a steady increase in scores during the study, with score change being more marked in the first year. Sharp and Larsen scores were highly correlated (r(s) = 0.96). Correlations of both scores with the Poznanski score were moderate to high (r(s) from -0.62 to -0.72). Radiologist score was correlated at borderline-high level with both Sharp (r(s) = 0.70) and Larsen (r(s) = 0.71) scores. Sharp and Larsen score change from baseline to final visit was moderately to highly correlated with the number of joints with active arthritis and restricted motion and the Childhood Health Assessment Questionnaire score at final visit. CONCLUSION: Our results demonstrate that the Sharp and Larsen scoring systems are potentially reliable and valid for assessment of radiographic progression in patients with polyarticular JIA.

Ultrasound of the joints.

High-frequency ultrasound is now considered an excellent modality to image normal tendons, muscles, and peripheral nerves as well as to diagnose a wide variety of pathological conditions affecting these structures. Although US is limited in the visualisation of some intra-articular structures, it can be a useful tool in joint disease assessment. Ultrasound has some advantages over other imaging modalities including time- and cost-effectiveness, superior spatial resolution, dynamic examination and the possibility to perform the examination in a comfortable position for the patient. The aims of this review are twofold: firstly, to present the normal US appearance of the joint structures that are susceptible to US examination, including the joint surfaces, intra-articular structures such as menisci and other fibrocartilages, capsule and ligaments; and secondly, to show the US appearance of the most commonly encountered joint disorders and discuss the role of US in the imaging strategy of joint disorders.

US of the shoulder: non-rotator cuff disorders.

The most common indication for shoulder ultrasonography (US) is the diagnosis of rotator cuff disease. However, there is a spectrum of non-rotator cuff abnormalities that are amenable to US examination, including instability of the biceps tendon, glenohumeral joint, and acromioclavicular joint; arthropathies and bursites (inflammatory diseases, degenerative and infiltrative disorders, infections); nerve entrapment syndromes; and space-occupying lesions. Many of these conditions may be overlooked clinically or can even mimic rotator cuff tears, and US can help redirect the diagnosis if a complete shoulder examination rather than a simple rotator cuff assessment is performed. In addition, US can be remarkably helpful in guiding either needle aspiration procedures or local injection therapy in patients with synovial processes. Although radiography, magnetic resonance (MR) imaging, and computed tomographic and MR arthrography are effective modalities for the evaluation of non-rotator cuff disorders, US is both less costly and less invasive and will likely be used more frequently in this setting as experience increases. Once adequate radiographs have been obtained to exclude apparent bone disorders, high-resolution US should be the first-line imaging modality in the assessment of non-rotator cuff disorders of the shoulder, assuming the study is performed with high-end equipment by an experienced examiner.