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.

Expression of antioxidant molecules after peripheral nerve injury and regeneration.

Oxidative stress is considered to be one of the main causes of neural damage after injury. However, little is known about the changes in mRNA expression of antioxidant molecules that occur after injury and regeneration of the peripheral nerve. In the present study, the rat median nerve was transected, and transcriptional changes were studied at day 6 and day 12 after injury in both the proximal and the distal stumps, in the absence or presence of microsurgical repair. The expression profiles of the following genes were investigated: three metallothionein isoforms (MT-1, MT-2, and MT-3), the main antioxidant enzymes (catalase, superoxide dismutase, and glutathione-S-transferase), and the marker of cellular damage poly(ADP-ribose) polymerase-1 (PARP-1). The results showed that, in the proximal nerve stump, MT-3 mRNA expression was significantly and markedly up-regulated in the absence of surgical repair, whereas MT-1 and MT-2 showed significant down-regulation. In the distal nerve portion, mRNA expression of all MT isoforms decreased significantly in the absence of microsurgical reconstruction, whereas, after repair, MT-3 mRNA expression alone was up-regulated. Expression of all the antioxidant enzymes decreased significantly after repair in the proximal nerve portion, but a significant general increase in their mRNA expression was revealed in the distal nerve stump. PARP-1 expression was significantly up-regulated in the proximal nerve portion without repair but dramatically reduced after reconstruction. In contrast, PARP-1 expression increased markedly in the distal stump after surgical repair. Taken together, these findings indicate that antioxidant molecules are differentially modulated and might, therefore, play an important role in peripheral nerve injury and regeneration.

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.

Correction of forearm deformities in congenital ulnar club hand: one-bone forearm.

PURPOSE: To describe our experience in the correction of congenital ulnar club hand, using the one-bone forearm procedure. METHODS: Fifteen cases of congenital ulnar club hand treated at Gaslini Children's Hospital of Genoa, Italy, from 1996 to 2008 were evaluated retrospectively. The one-bone forearm procedure was proposed for all 9 cases of type 2 (following the Bayne classification) and then performed in 8 patients with an average age of 5.5 years (range, 3-12 y). At surgery, the patients presented paradoxical hyperextension of the elbow (up to 45° of extension). RESULTS: Average follow-up was 5.3 years (range, 1 to 13 y). Union of the osteotomy was obtained in all cases. In 7 cases, union occurred in an average of 65 days (range, 45-90 d); in 1 case (surgery at 12 y of age), union was delayed, with recovery 5.5 months after surgery and no need for further surgical procedures. All treated cases showed improvement of forearm function and of grasping ability of the hand (generally tridactyl). In addition, the paradoxical hyperextension movement that was present before surgery disappeared in all patients. Long-term radiographic follow-up showed in all cases the formation of a structure that was morphologically similar to that of the previously resected radial head. CONCLUSIONS: The one-bone forearm procedure improves malformed forearm functions, thus increasing the possibility of carrying out daily life activities. The creation of the one-bone forearm should be preceded by the release of the distal ulnar anlage, which maintains fixed wrist deformity; this procedure should be performed within the first year of life.

Hand and upper limb anomalies in Poland syndrome: a new proposal of classification.

BACKGROUND: The Poland anomaly (PA) comprises unilateral absence or hypoplasia of the pectoralis major muscle and a variable degree of ipsilateral hand and upper limb anomalies. Various hand and upper limb anomalies classifications in PA have been previously published. In this work, a new classification of hand and upper limb anomalies in PA is proposed, on the basis of the clinical and instrumental evaluation of 175 patients. METHODS: The patients have been followed by a multidisciplinary approach, consisting in orthopaedic, surgical, and genetic evaluation and chest, upper limb, and ultrasound examination of major and minor pectoralis muscles, heart, and kidney. RESULTS: Hand and upper limb anomalies were classified in 8 groups on the basis of the clinical degree of severity and on the basis of the presence of coexisting associated anomalies. Data regarding the sex and laterality, previously reported in the medical literature, were confirmed by our analysis. Etiopathogenetic mechanisms leading to the anomaly are discussed. CONCLUSIONS: The proposed classification is derived from the observation of the widest group of patients described in the medical literature. Our proposal could help in the management of patients affected by Poland syndrome and in understanding etiological and pathologic aspects of the disease. LEVEL OF EVIDENCE: IV.

Open Galeazzi's Fracture-Dislocation in a 13-Year-Old Boy: A Case Report.

Background Galeazzi's fracture-dislocation (GFD) is a rare and complex injury consisting of a radial fracture associated with distal radioulnar joint (DRUJ) dislocation. Case Description We are presenting a case of a boy, who at the onset showed an open GFD and his assessment after a 1-year follow-up. As a treatment, closed reduction and long-arm cast were performed. At the last follow-up, the patient presented a complete recovery of range of motion and function of the affected wrist. Literature Review To the best of our knowledge, in the current literature, there are no reported cases of open GFD. Clinical Relevance Although open GFD is rare this case report may suggest orthopaedic surgeon how to approach and manage it.

Corrective Procedure for Flexion Contracture of the Elbow in Neonatal Palsy Sequelae: Long-term Follow-up.

BACKGROUND: Aim of this paper is to validate a procedure for correcting elbow flexion contracture in patients suffering from brachial plexus neonatal palsy sequelae during their teens. Elbow flexion contracture represents an unsolved problem in the natural history of obstetric brachial plexus palsy (OBPP) because of the consistent deformity recurrence. Following a previous paper, in which an original technique was proposed in a small sample of patients, the authors show the possible correction of the deformity in a larger group of patients. METHODS: The procedure includes a combination of a posterior approach to the elbow with olecranon tip section and an anterior one with capsulotomy and soft tissue release to improve elbow range of motion. A series of 26 patients, who underwent the procedure, were checked out in medium and long term. Collected data were age, type of brachial plexus palsy, length of hospitalization, duration of surgery, preoperative and postoperative elbow range of motion, preoperative and postoperative DASH scores and satisfaction scores. Explaining further details about the procedure, the Authors report their results, including a statistical analysis. RESULTS: At the final follow-up, the mean increase of elbow extension was about 22°. Functional outcomes were successful as well, with a mean increase of 10 points of DASH score. Over 75% of patients were fully satisfied with their outcome. CONCLUSIONS: The outcome has confirmed the good efficacy of the procedure in increasing elbow extension but also in improving cosmetic appearance in adolescents suffering from flexed elbow in OBPP sequelae.

The Cervico-Parasternal Thoracotomy (CPT): A New Surgical Approach for the Resection of Cervicothoracic Neuroblastomas.

Cervicothoracic neuroblastomas (NBs) pose unique surgical challenges due to the complexity of the neurovascular structures located in the thoracic inlet. To date, two main techniques have been reported to completely remove these tumours in children: the trans-manubrial and the trap-door approaches. Herein, the authors propose a third new surgical approach that allows a complete exposure of the posterior costovertebral space starting from the retro-clavicular space: Cervico-Parasternal Thoracotomy (CPT). The incision is made along the anterior margin of the sternocleidomastoid muscle until its sternal insertion, and then the incision proceeds vertically following the ipsilateral parasternal line. The major pectoralis muscle is detached, and the clavicle and the ribs are disarticulated from their sternal insertions. Following an accurate isolation of the major subclavian blood vessels and the brachial plexus roots, the tumour is then completely exposed and resected by switching from a frontal to a lateral view of the costo-vertebral space. By adopting this technique, five cervicothoracic NBs were completely resected in a median operative time of 370 min (range: 230-480 min). By proceeding in safety with the heart apart, neither vascular injuries nor nerve damages occurred, and all patients were safely discharged in a median postoperative time of 11 days (range: 7-14 days). At the last follow-up visit (median: 16 months, range: 13-21 months), all patients were alive and disease-free.

Hand and Upper Limb Malformations in Italy: A Multicentric Study.

Background: Although hand and upper limb malformations are quite frequent, up to now very few reports have been published on epidemiology. The aim of this study is to evaluate the number of infants who presented with hand and upper limb malformations from 2010 to 2015 in Italy. Methods: A retrospective analysis of a pediatric population presenting with hand and upper extremity malformations was carried out, gathering reports achieved from eight Italian Centers of pediatric hand surgery. Other factors such as gender, date and region of birth, family distribution of malformations and associated syndromes, were analysed. Results: Out of 3,100,421 live births, 765 children presented with hand and upper limb malformations. The incidence was 2,5/10,000 live births with a predominance of males and the right side. Radial polydactyly was the anomaly with the highest percentage, closely followed by simple syndactyly, simbrachidactyly and complex syndactyly. Less common conditions were the triphalangic thumb, thumb in palm, proximal radioulnar synostosis and Sprengel deformity. Inheritance of and familial predisposition to those malformations was recorded in 25 cases, while 84 children presented with syndromes related to hand anomalies. Conclusions: In conclusion the incidence of hand and upper extremity malformations in Italy is lower than that registered in other countries. The retrospective nature of the study combined with the fact that some defects frequently evade pediatric hand surgeon consultations are some possible limitations of the study. However, our data confirmed that, in spite of the decrease in the birth rate in Italy, the trend of congenital hand disorders maintained a stable trend. We aim to integrate this study with a prospective analysis and to involve the institutional health authorities in other countries so as to register the correct incidence of hand and upper extremity defects.

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.

Sciatic nerve injection palsy in the child: early microsurgical treatment and long-term results.

Sciatic nerve injury caused by intramuscular injection in the gluteal region in the child seems as a sensory-motor palsy of the lower limb of variable degree. In preterm children or in children with severe perinatal distress, requiring intensive care, a drop foot is often missed or misdiagnosed as a malformative clubfoot or late diagnosed. Intramuscular drug injection (mainly antibiotics) during early infancy is another cause of injury. There are very few literature reports on postinjection trauma and on therapeutic indications in the child. The Authors report their experience in early microsurgical exploration of the sciatic nerve. From 1990 to 2004, we observed at different times from diagnosis 17 children with sciatic nerve palsy following intramuscular injection. Nine of them underwent nerve exploration surgery in the gluteal region (neurolysis in seven and nerve grafting in two). Conservative treatment was successful in only three cases showing early signs of recovery (at about 3 months of life). Complete recovery was observed only in five early treated cases, while late treated cases had only mild improvement after surgery. During surgery, anatomical variations predisposing to nerve injury were observed. The authors havingobserved better results and faster recovery in the early treated patients, stress the importance of a rapid therapeutic decision to avoid or limit foot deformities, sensory defects and lower limb length discrepancy due to paralysis during growth.

Upper limb nerve injuries in developmental age.

Our series includes 105 children with peripheral nerve injuries of the upper limb due to trauma. The aim of this study is to validate our therapeutic approach to peripheral nerve injuries of the upper limb in children and to identify the suitable waiting time before surgical exploration. Case series examination included evaluation of (1) type of lesion; (2) topographical site of nerve injury; (3) motor and sensory outcome; (4) recovery time; (5) results after surgery. Open injuries (Sunderland V) received immediate treatment with direct suturing or nerve grafts or biological tubules in case of loss of nerve substance. After closed nerve injury, a waiting period of variable duration should precede surgery. Most of the cases had peripheral nerve injuries associated to fracture and cutting lesions followed by injuries due to other causes. Open or closed injuries of the median and radial nerves had a generally favorable prognosis, whereas ulnar nerve injuries (both isolated and associated) had a poor prognosis. Stable skeletal fixation is essential in fractures at risk of nerve involvement. During nerve exploration, secondary surgery interventions were never associated. In the absence of adequate clinical and instrumental response, the authors suggest to resort to nerve surgery at 6 months from injury to accelerate recovery time. Secondary surgery should be delayed as patient's recovery time can be very long. (c) 2009 Wiley-Liss, Inc. Microsurgery, 2009.

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.

Correction of elbow flexion contracture by means of olecranon resection and anterior arthrolysis in obstetrical brachial plexus palsy sequelae.

The authors have developed a particular surgical technique (olecranon bone resection together with anterior elbow arthrolysis) to increase the elbow's range of motion in adolescents and young adults suffering from elbow flexion contracture in obstetrical palsy sequelae. The surgical procedure was carried out in a preliminary group of 11 patients. The original procedure included a double incision: first of all by means of a posterior approach to resect the tip of the olecranon and then another incision carried out through the anteromedial aspect of the elbow, with a view to performing the anterior capsulotomy. Preoperatively, the average clinical elbow extension was 64.9°, whereas after surgery, the value increased to 43.63°. The average DASH score was 38.27 points before surgery, whereas it decreased to 29.98 points after surgery. A statistical analysis was also carried out to confirm the outcome. The procedure is reliable, is not time-consuming, and does not lead to any major complications.

Nerve Transfer in Delayed Obstetrical Palsy Repair.

OBJECTIVE: When root avulsions are detected in children suffering from obstetrical brachial plexus palsy (OBPP), neurotization procedures of different nerve trunks are commonly applied in primary brachial plexus repair, to connect distally the nerves of the upper limbs using healthy nerve structures. This article aims to outline our experience of neurotization procedures in OBPP, which involves nerve transfers in the event of delayed repair, when a primary repair has not occurred or has failed. In addition, we propose the opportunity for late repair, focusing on extending the time limit for nerve surgery beyond that which is usually recommended. Although, according to different authors, the time limit is still unclear, it is generally estimated that nerve repair should take place within the first months of life. In fact, microsurgical repair of OBPP is the technique of choice for young children with the condition who would otherwise have an unfavorable outcome. However, in certain cases the recovery process is not clearly defined so not all the patients are direct candidates for primary nerve surgery. METHODS: In the period spanning January 2005 through January 2011, among a group of 105 patients suffering from OBPP, ranging from 1 month to 7 years of age, the authors have identified a group of 32 partially recovered patients. All these patients underwent selective neurotization surgery, which was performed in a period ranging from 5 months to 6.6 years of age. RESULTS: Late neurotization of muscular groups achieved considerable functional recovery in these patients, who presented with reduced motor function during early childhood. The said patients, with the exception of five, would initially have avoided surgery because they had not met the criteria for nerve surgery. CONCLUSION: We have concluded that the execution of late nerve surgical procedures can be effective in children affected by OBPP.

Use of tubulization (nerve conduits) in repairing nerve defects in children.

BACKGROUND: Direct neurorrhaphy, nerve grafting interposition and neurotization are the options for nerve repair in children, whereas few reports about using nerve conduits (tubulization) are referred to pediatrics in the literature. The authors present their experience about nerve repairing by means of nerve tubes during the developmental age when the harvesting of nerve grafts and also vein grafts of adequate caliber for bridging nerve defects is difficult. A critical review of their case series offers indications for using nerve conduits in pediatrics. MATERIALS AND METHODS: Fifteen patients were treated using the nerve tubulization; nine patients were affected by obstetrical brachial plexus palsy (OBPP) while six were suffering from peripheral nerve injuries (PNIs). RESULTS: In patients suffering from OBPP, we observed 1 good, 3 fair and 5 bad results. In the PNI group, we observed 4 patients who had good results while only 2 had a bad outcome. No fair results were observed. CONCLUSIONS: In peripheral nerve repairing in children by using nerve conduits, the outcome has been widely effective even when dealing with mixed and motor nerve, thus nerve tubulization might be considered as an alternative to nerve grafting. Conversely, considering the uncertain result obtained in brachial plexus repairing, the conduits cannot be considered as a first choice of treatment in brachial plexus reconstruction.

Diaphyseal femoral fractures below the age of six years: Results of plaster application and long term followup.

BACKGROUND: In children less than 6 years, the treatment of femoral shaft fracture is often non surgical, using closed reduction and casting. The literature reports many experience about this type of trauma but none of these has a long term followup. We present a retrospective study on a group of femoral diaphyseal fractures treated nonsurgically in children up to 6 years of age, with a minimum of 10 year followup. MATERIALS AND METHODS: 48 cases (36 males/12 females) with femoral diaphyseal fractures treated between January 1988 and December 1998 were reviewed. Patients with fractures due to obstetrical trauma and pathologic fractures were excluded. The mean age of the patients was 3.3 ± 1.1 years (range 5 months-6 years). Right side was involved in 21 cases (44%), and left side in 27 cases (56%). In 34 cases (71%), closed reduction was performed and hip spica was applied with the hip and knee flexed to 45°. In 8 cases (17%), skeletal traction was applied to perform fracture reduction and the traction pin was embedded in plaster while in the remaining 6 cases (12%), the Delitala pressure apparatus was applied after casting. RESULTS: All fractures healed in our study. There were no complications (infection or vascular nervous issues, axial deviations, consolidation delays, or pseudoarthrosis). In 13 cases (27%), followup examinations showed mean lengthening of 1.3 ± 0.75 (range 0.5-2.5 cm) of the fractured lower limb. All these patients were treated with skin traction before treatment and presented with 2.08 ± 0.28 cm mean initial femoral shortening. In 1 case (2%) with 2.5 cm lengthening, epiphysiodesis of the ipsilateral knee was performed. No patients showed prolonged difficulty with gait disorders. CONCLUSION: On the basis of our results conservative treatment of femoral shaft fractures in children can be considered less invasive and safe procedure.

Intramedullary osteosynthesis for metaphyseal and diaphyseal humeral fractures in developmental age.

UNLABELLED: Diaphyseal and metaphyseal fractures of the humerus are relatively frequent in children. The treatment is often conservative, even in the case of displaced fractures for the high rate of spontaneous recovery of these fractures. The limits of nonsurgical treatment and its applications as well as the type of surgical treatment are controversial issues in the literature. The aim of this study is to review a series of metaphyseal and diaphyseal fractures of the humerus treated with intramedullary osteosynthesis, to discuss the results obtained and the problems found, and to propose some parameters that should be taken into account to choose the most appropriate osteosynthesis. The retrospective study was performed on a group of 105 proximal and distal metaphyseal fractures and of displaced diaphyseal fractures of the humerus (excluding epiphyseal trauma, supracondylar fractures, and pathologic fractures) treated from 2001 to 2005. Out of a total of 105 patients, only 22 had fracture reduction under anesthesia, followed by intramedullary osteosynthesis; in 11 cases, intramedullary osteosynthesis was performed using Kirschner wires and in the remaining 11 elastic nails were used. In all treated patients, fracture healing was achieved. In the patients treated with Kirschner wires, no complications were observed, whereas in the patients treated with intramedullary nails, there were three cases with involvement of the skin and subcutaneous layers at the nail insertion site and one case of temporary paralysis of the radial nerve disappearing spontaneously after 2 months. Considering the results obtained and the low number of technique-related complications (low anesthesiologic and infectious risk), we can conclude that intramedullary osteosynthesis is a simple, safe, and rapid method suitable at any age in childhood. LEVEL OF EVIDENCE: level IV.