An original preoperative orthopaedic management of a complex spinal deformity in a 16-year-old patient with spondyloepiphyseal dysplasia congenita.

PURPOSE: Spinal deformities in patients with Spondyloepiphyseal Dysplasia congenita are particularly challenging to treat. Addressing these deformities requires a holistic surgical strategy. The aim of this case report is to highlight an original preoperative protocol combining atlantoaxial instability stabilization by halo jacket with progressive correction of a thoracic kyphoscoliosis using continuous elongation by tension plaster cast as described by Stagnara. METHOD: A 16-year-old patient with spondyloepiphyseal dysplasia congenita presenting a severe thoracic kyphoscoliosis associated with atlantoaxial instability causing cervical myelopathy was managed through a preoperative protocol combining a halo jacket with a Stagnara elongation cast allowing progressive correction of the kyphoscoliosis while stabilizing the cervical instability. RESULTS: The preoperative protocol allowed a safer and a more effective surgical spine fusion, reducing neurological risks, improving the final correction, and offering better postoperative recovery. Clinical and radiological solid fusion was observed at 3-year-follow-up with significant improvement of the patient's quality of life. CONCLUSION: This case report highlights the effectiveness of the preoperative preparation combining a halo jacket with a Stagnara elongation cast to safely stabilize the cervical spine while correcting the thoracic kyphoscoliosis. This strategy can serve as a valuable tool for spine teams when addressing complex spinal deformities particularly in this patient with SEDc. LEVEL OF EVIDENCE: Level IV.

Safety of Laparoscopic Cholecystectomy for Cholecystitis during Pregnancy.

Objectives: The aim of this study is to evaluate the safety of laparoscopic cholecystectomy to treat acute cholecystitis during pregnancy. Materials and Methods: We conducted a retrospective multicenter study including pregnant women with acute cholecystitis managed in surgery departments in Tunisia from January 1, 2015, to December 31, 2019. Results: Seventeen centers of surgery department participated in this study including 107 cases of acute cholecystitis. The average maternal age was 30.5 years. Nonoperative management was performed in eight patients, whereas 99 other patients had surgery. Postoperative follow-up was uneventful in 93.8% of cases and eventful in 6.2% of cases. There was no mortality as far. A medical complication occurred in two patients with a medical morbidity rate of 1.7%. It was about thromboembolic disease. A surgical complication occurred in two other patients with a surgical morbidity rate of 1.7%. It was about intraperitoneal infection in one case and biliary collection in the other case. In univariate analysis, variables related significantly to maternal complication were: age equal or over 35 years old (P = 0.001), jaundice (P = 0.024), C-reactive protein value equal or over 20 mg/L (P = 0.05), and biliary peritonitis (P = 0.05). In multivariate analysis, independent variable predictive of maternal complications was age equal or over 35 years old (P = 0.003), jaundice (P = 0.003), and biliary peritonitis (P = 0.011). Conclusion: Laparoscopic cholecystectomy for cholecystitis can be safely achieved in pregnant women with low rates of morbidity and mortality. This study showed that independent variable predictive of maternal complications was age equal or over 35 years old, jaundice, and biliary peritonitis.

Reconstruction of isolated hypoplasia of the patella by a modified Galeazzi procedure: a case report.

BACKGROUND: Isolated Patellar Aplasia Hypoplasia is a very rare autosomal dominant disorder. Its treatment depends on the clinical manifestations that can vary widely. The lack of active extension, which can be responsible for frequent falls due to a knee instability, is the most frequent and disabling manifestation. We report an original technique that is a modification of the Galeazzi technique for recurrent dislocation of the patella to gain active extension in case of PTLAH. CASE REPORT: A 7-year-old Caucasian boy with isolated Patellar Aplasia Hypoplasia and an extension lag of the right knee has been treated by a modified Galeazzi technique. The tendons of the semi-tendinous and gracilis muscles have been harvested and their distal insertion was kept intact. Both tendons were fixed over the top of the patella to restore knee active extension. After 6 years of follow up the patient is symptom free with a strong active extension of the operated knee. CONCLUSION: Reconstruction of isolated hypoplasia of the patella by a modified Galeazzi procedure is a safe and reliable technique for skeletally immature patients offering satisfying long-term outcomes.

Case report: Exome sequencing revealed disease-causing variants in a patient with spondylospinal thoracic dysostosis.

Background: Spondylocostal dysostosis is a rare genetic disorder caused by mutations in DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2. A particular form of this disorder characterized by the association of spondylocostal dysostosis with multiple pterygia has been reported and called spondylospinal thoracic dysostosis. Both disorders affect the spine and ribs, leading to abnormal development of the spine. Spondylospinal thoracic dysostosis is a rare syndrome characterized by the association of multiple vertebral segmentation defects, thoracic cage deformity, and multiple pterygia. This syndrome can be considered a different form of the described spondylocostal dysostosis. However, no genetic testing has been conducted for this rare disorder so far. Methods: We report here the case of an 18-month-old female patient presenting the clinical and radiological features of spondylospinal thoracic dysostosis. To determine the underlying genetic etiology, whole exome sequencing (WES) and Sanger sequencing were performed. Results: Using WES, we identified a variant in the TPM2 gene c. 628C>T, already reported in the non-lethal form of multiple pterygium syndrome. In addition, following the analysis of WES data, using bioinformatic tools, for oligogenic diseases, we identified candidate modifier genes, CAP2 and ADCY6, that could impact the clinical manifestations. Conclusion: We showed a potential association between TPM2 and the uncommon spondylocostal dysostosis phenotype that would require further validation on larger cohort.

Posterior cruciate ligament avulsion associated with an epiphyseal fracture of the proximal fibula: a case report of a 13-year-old child.

Posterior cruciate ligament (PCL) avulsion fractures are rare among the pediatric population. Reported PCL injury incidence varies from 1 to 40% depending on the study population. PCL lesions can be isolated or associated with other ligamentous lesions, which makes their management challenging. Knee ligament reconstruction is essential to restore knee stability and, thus, prevent future menisci and cartilage degeneration. However, surgical management of these injuries can lead to subsequent iatrogenic growth disturbances. Case presentation: The authors describe the case of a 13-year-old child involved in a sports accident causing a PCL avulsion fracture associated with an epiphyseal fracture of the proximal fibula resulting from an incomplete peel-off injury of the lateral collateral ligament. The patient was scheduled for open reduction and internal fixation on the same day of the presentation. A long-leg cast was then applied for 6 weeks. By 3 months postoperatively, the patient regained full range of motion, and return to sport was possible 6 months after the surgery. Conclusion: In children and adolescents, PCL avulsion fractures are often associated with other occult lesions. Although good functional and clinical outcomes using operative management for these lesions are reported, specific treatment recommendations are lacking in skeletally immature patients.

Growing rods for early-onset scoliosis in Ehlers-Danlos disease.

PURPOSE: To study the results and complications of Traditional Growing Rods (TGR) for the treatment of Early-Onset Scoliosis (EOS) in patients with Ehlers-Danlos syndrome (EDS). METHODS: This is a retrospective study of patients with EDS treated for EOS between 2012 and 2018 by TGR. For each patient, we evaluated the evolution of the Cobb angle of the main coronal curve before the first surgery, postoperatively and at the last follow-up. We also noted every complication. RESULTS: Four patients have been evaluated. Age at the index surgery ranged from 3- to 6-year-old. All the patients had a Kyphoscoliosis. The preoperative Cobb angle of the main coronal curve ranged from 70° to 104°. Prior to surgery, a progressive correction of the spinal deformity by Halo-gravity traction was performed for all patients. One patient had several complications with a poor result after final fusion. Three patients did not sustain any complication and presented good results. Follow-up ranged from 3 to 8 years. For two of our patients, further lengthening procedures are still needed. CONCLUSIONS: TGR is a good surgical option for the treatment of EOS in EDS. A progressive preoperative correction is recommended. Anchor-related complications must be minimized in these patients with an important kyphosis. Level of evidence Level IV.

Case Report: Caecal volvulus management from diagnosis to treatment in a young patient.

Caecal volvulus (CV) is a rare cause of intestinal obstruction, defined by an axial torsion of the caecum, ascending colon, and terminal ileum around the mesenteric vascular pedicles, leading to ischemia and bowel necrosis. A 20-year-old woman, with no significant medical history, was admitted for generalized abdominal pain evolving for three days, along with constipation and abdominal distension, but with no vomiting. Physical examination showed a generalized abdominal tenderness with no rigidity or rebound tenderness, associated with abdominal distension and tympanic upon percussion. Laboratory findings were within normal limits. An abdominal computed tomography scan revealed distension of a loop of the large bowel with its long axis extending from the right lower quadrant to the epigastrium or left upper quadrant. Colonic haustral pattern was absent. An abdominal computed tomography scan showed a rounded focal collection of air-distended bowel with haustral creases in the upper left quadrant. In addition, spiraled loops of the collapsed cecum (giving a whirl sign) were noted, along with low-attenuating fatty mesentery from the twisted bowel. The patient underwent an emergency laparotomy and caecectomy using GEA 80 charges. The patient had no complaints post-operation. CV is a rare cause of bowel obstruction, mainly caused by an exceedingly mobile caecum. Despite its rareness, CV represents the second most common cause of large bowel volvulus, behind sigmoid volvulus. For acute obstruction by CV, it is hard to differentiate it clinically from obstruction of the small bowel; therefore, radiological exams are needed. Surgery is the gold standard treatment for CV. We report a rare case of CV to highlight the rarity of this pathology, specify its diagnostic and therapeutic means, and its clinical and biological evolution.

Ankle sprain injury in child and adolescent: Diagnostic pitfalls.

Introduction and importance: Sprained ankles in children and adolescents are rare. Certain diagnostic pitfalls must arise in the mind of the clinician because many differential diagnoses must be confirmed or refuted urgently. Among them, the infectious osteoarticular pathology including acute hematogenous osteomyelitis of the tibia or distal fibula and septic arthritis of the subtalar joint.The main purpose of this work, through four clinical cases, we will discuss diagnostic pitfalls in the course of ankle trauma in children and adolescents. Case presentation clinical: In this work, we have demonstrated through four cases some diagnostic errors in the context of ankle trauma in children and adolescents. Infectious and malignant tumor pathologies are real diagnostic and therapeutic emergencies. For all these cases, the initial diagnosis was a sprained ankle following a gambling or sports accident. Discussion: Ankle trauma in children and adolescents is a frequent reason for consultation in emergencies. The fear of the orthopedic surgeon is to miss a serious pathology and wrongly make the simple diagnosis of a sprained ankle. Temperature measurement must be systematic. The clinical examination must be meticulous. The interpretation of the radiograph must be cautious. Acute hematogenous osteomyelitis and malignant tumor pathology should be on the surgeon's mind. Conclusion: We have shown through these four examples that a serious pathology can simulate a sprain. Hence, a careful analysis of clinical, biological and radiological elements is the only guarantee of adequate care.

Acute hematogenous osteomyelitis in children: Management of pandiaphysitis with extensive bone destruction: A case series of thirteen child.

Introduction: and Importance: Acute hematogenous osteomyelitis (AHO) poses a public health problem in severe forms from the outset or with delayed diagnosis. The aim of this work is to describe the management of pandiaphysitis with extensive bone destruction by the Ilizarov external fixator and antibiotics and to evaluate the results. Methods: This is a retrospective, descriptive, cross-sectional and single-center study. It was performed over a seven-year period. We included children with acute hematogenous osteomyelitis complicated by pandiaphysitis of the long bones with extensive bone necrosis. All patients underwent stabilization with an Ilizarov external fixator and antibiotic therapy adapted to the antibiogram in ten cases. One patient had the induced membrane technique. All the patients underwent dynamization of the Ilizarov external fixator followed by immobilization with a cast or a splint for the lower limb. Outcomes: 13 medical files were collected during the study period. The sex ratio was 1.6, the average age was 7.56 years. Three localization sites: humerus for 3 cases, femur for 3 cases and tibia for 7 cases. The germ has been identified in ten cases. Methicillin-resistant staphylococcus aureus was the most common. Bone consolidation is obtained in all cases with an average delay of ten months. Conclusion: The Ilizarov external fixator associated with antibiotics has proven its effectiveness in the management of pandiaphysitis with extensive bone destruction. This method is an alternative in the therapeutic arsenal available to pediatric orthopedic surgeons. Level of evidence: IV, Case series.

Craniofacial Malformations as Fundamental Diagnostic Tools in Syndromic Entities.

Background: A long list of syndromic entities can be diagnosed immediately through scrutinizing the clinical phenotype of the craniofacial features. The latter should be assisted via proper radiological interpretations. Patients and Methods: Different children aged from 1 month to 12 years were referred to our departments seeking orthopedic advice. Primarily, all received variable false diagnoses in other institutes. Two unrelated boys of one month and 12 months were falsely diagnosed as having positional plagiocephaly associated with contractures of idiopathic origin. Two unrelated boys of 14 months and 2 years were diagnosed with pseudo-hydrocephalus and non-specific syndrome, and were referred to explore their skeletal development. Two unrelated girls of 4 years old and 12 years old presented with multiple contractures were referred because of progressive scoliosis. A 4-year-old girl was referred with a false provisional diagnosis of facial diplegia. All children underwent detailed clinical, radiological and tomographic phenotypic characterizations and genetic testing, respectively. Results: Idaho syndrome (craniosynostosis associated with multiple dislocations) was the final diagnosis in the two unrelated boys with plagiocephaly and multiple contractures. Two children falsely diagnosed with pseudo-hydrocephalus and non-specific syndrome, were diagnosed with Silver-Russell syndrome (RSS). Contractural arachnodactyly Beals (CAB) was confirmed as the definitive diagnosis in the two unrelated girls with progressive scoliosis and multiple contractures. Parry-Romberg syndrome (PRS) associated with congenital lumbar kyphosis was the final diagnosis of the girl with the diagnosis of facial diplegia. Hypomethylation of ICR1 was confirmed in the RSS patients. Whole exome sequencing (WES) revealed a heterozygous mutation in the PRS patients. WES and array-CGH showed that no relevant variants or copy number variations (CNV) were identified in the CAB patients. Conclusions: On the one hand, newborn children can manifest diverse forms of abnormal craniofacial features, which are usually associated with either major or minor dysmorphic stigmata. A cleft lip/ palate is a major craniofacial malformation, and frontal bossing or a disproportionate craniofacial contour can be falsely considered as a transient plagiocephaly, which is spontaneously resolved by time. On the other hand, many physicians fall into the problem of deeming a countless number of diseases, such as contractures, as an idiopathic or non-specific syndrome. The latter stems from limited clinical experience. Therefore, failing to establish between the onset of the deformity and other inexplicit abnormal features that the patient or their immediate families or relatives carry is the final outcome. In this study, we used, for the first time, a reconstruction CT scan to further delineate the congenital disruption of the craniofacial anatomy and the other skeletal malformation complex.

Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome.

Escobar syndrome is a rare, autosomal recessive disorder that affects the musculoskeletal system and the skin. Mutations in the CHRNG and TPM2 genes are associated with this pathology. In this study, we conducted a clinical and genetic investigation of five patients and also explored via in silico and gene expression analysis their phenotypic variability. In detail, we identified a patient with a novel composite heterozygous variant of the CHRNG gene and two recurrent mutations in both CHRNG and TPM2 in the rest of the patients. As for the clinical particularities, we reported a list of modifier genes in a patient suffering from myopathy. Moreover, we identified decreased expression of IGF-1, which could be related to the short stature of Escobar patients, and increased expression of POLG1 specific to patients with TPM2 mutation. Through this study, we identified the genetic spectrum of Escobar syndrome in the Tunisian population, which will allow setting up genetic counseling and prenatal diagnosis for families at risk. In addition, we highlighted relevant biomarkers that could differentiate between patients with different genetic defects.

Calcaneal lengthening osteotomy in the management of idiopathic flatfoot in children: cCase series of twenty-one feet.

INTRODUCTION: Flatfoot is a frequent reason for consultation in pediatric orthopedics. The calcaneal lengthening osteotomy according to the EVANS technique is a therapeutic alternative. The objective of this work was to evaluate the short and medium term clinical and radiological results of calcaneal lengthening osteotomy in children with idiopathic flat foot valgus. METHODS: This study concerned 12 children and 15 ft treated surgically by calcaneal lengthening osteotomy by an orthopedic surgeon in a pediatric orthopedic surgery center. The evaluation of the results was clinical according AOFAS score and radiological. RESULTS: The deformity was reducible in all of our patients. The mean preoperative AOFAS score was 61, postoperatively 90. The overall result was excellent in 11 cases (11 ft) and good in 4 cases. The postoperative radiological result was close to normal values. CONCLUSION: Calcaneal lengthening osteotomy is a reliable and recommended technique for the correction of symptomatic idiopathic flatfoot. LEVEL OF EVIDENCE: IV, Case series.

Right Colon Clear Cell Carcinoma of Müllerian Type.

Clear cell carcinoma (CCC) is usually seen in tissues originating from the paramesonephric (Müllerian) ducts such as the kidneys, the ovaries, the cervix and the vagina. The pathogenesis has not yet been elucidated. The diagnostic hallmark is the clear cytoplasm. Primitive CCC of the colon is a very rare entity. There are two types of CCC of the colon; the intestinal type and the Müllerien type. The differential diagnosis arises mainly with secondary metastases of renal or ovarian origin. Immunohistochemistry allows retaining the primitive character. The treatment is not yet consensual. It depends on the type of tumor and its stage. The treatment is based on surgery and possibly chemotherapy. We report the case of a 75-year-old female patient who underwent surgery for a tumor of the ascending colon. Microscopic examination concluded an extensively necrotic carcinomatous growth which infiltrated all the layers of the intestinal wall and the peritoneum. The tumor was made of clusters and spans of clear cells which were separated by thin conjunctivo-vascular septa. The tumor cells were round to polygonal with a clear, optically empty, pseudo-vegetative (physaliferous) cytoplasm. Immunohistochemistry study showed a positive staining with CK7 and a negative staining with CK20, CDX2, PAX8, P63, CD10, chromogranin, and synaptophysin. We performed a Medical Literature databases (Pubmed and Google Scholar) research. Only forty-two cases were reported in English literature. The main age is 55.7 (25-89). The sex ratio is one, but female cases were younger (52 vs. 61). The rectum is the most involved site. The left colon location is more frequent than the right one. The Müllerian type was found only at the level of the left colon and rectum. There was no CCC in the right colon of Müllerien type. The case we report herein is the first right colon CCC which is positive in CK7 staining.

Gayet-Wernicke's encephalopathy complicating prolonged parenteral nutrition in patient treated for colonic cancer - a case report.

BACKGROUND: Gayet-Wernicke's encephalopathy (GWE) is a neurological pathology caused by a Thiamine deficiency. While it is most often related to chronic alcoholism, GWE can occur in any situation that results in thiamine deficiency. It is a fairly common pathology that is frequently underdiagnosed and therefore under-treated, and is associated with a high mortality and morbidity rate. In the absence of pathognomonic signs, the diagnosis of GWE relies on a range of clinical, biological and radiological assessments. GWE is considered a medical emergency. We present a case of Gayet-Wernicke's Encephalopathy resulting from complete parenteral nutrition in an undernourished North African male operated for a left colon tumor. Through this report, our aim was to put the light on this often underknown disease and to remind the interest of thinking about this pathology in patients at risk of undernourishment especially in oncology. CASE PRESENTATION: A 66-year-old North African male with no personal or family history was operated for a sigmoid colon tumor. He was put on exclusive parenteral nutrition on day thirteen post-operatively and presented with a GWE on day sixteen post-operatively. The patient was treated with intravenous vitamin B1 on day eighteen post-operatively and deceased on day twenty-four post-operatively. CONCLUSIONS: Although most often associated with chronic alcoholism, GWE occurs in any situation where there is an increased energy demand or decreased nutritional intake especially in oncology. GWE is common but under-diagnosed and remains lethal if not treated urgently, hence the importance of prophylactic treatment.

Torticollis in Connection with Spine Phenotype.

PURPOSE: Torticollis is not of uncommon occurrence in orthopaedic departments. Various theories and studies concerning the pathogenesis of the deformity have been suggested. We aimed to highlight and discuss the underlying cervical and spine malformation complex in correlation with torticollis via radiographic and tomographic analysis and its connection with a specific syndromic entity. METHODS: Torticollis has been recognised in six patients (2 boys and 4 girls with an age range of 14-18 years), in addition to a couple of parents manifested persistent backpain. A variable spine malformation complex was the main reason behind torticollis. In addition, some patients manifested plagiocephaly, facial asymmetry and scoliosis/kyphoscoliosis. In some patients, conventional radiographs were of limited value because of the overlapping anatomical structures. Three-dimensional reconstruction CT scanning was the modality of choice, which enlightens the path for the phenotypic characterisation. RESULTS: A 16-year-old-boy presented with torticollis in correlation with pathologic aberration of the spine cartilaginous stage was analysed via 3DCT scan. Comprehensive clinical and radiological phenotypes were in favour of spondylomegepiphyseal dysplasia. The genotype showed a mutation of the NKX3-2 (BAPX1) gene compatible with the diagnosis of spondylo-meg-epiphyseal-metaphyseal dysplasia. His younger male sibling and parents were heterozygous carriers. In two patients with pseudoachondroplasia syndrome, in which odontoid hypoplasia associated with cervical spine synchondrosis causing life-threatening torticollis, Cartilage oligomeric matrix protein (COMP) gene mutation was identified. MURCS syndrome has been diagnosed in two unrelated girls. Torticollis associated with cervical kyphosis was the major presentation since early childhood. Interestingly, one girl showed omovertebral bones of the lower cervical and upper thoracic spine. Her karyotype manifested a balanced translocation of 46 XX, t (14q; 15q). CONCLUSION: To detect the underlying etiological diagnosis of torticollis, a skeletal survey was the primary diagnostic tool. Conventional radiographs of the craniocervical junction and spine resulted in confusing readings because of the overlapping anatomical structures. Cranio-cervical malformation complex could have serious neurological deficits, especially for children with indefinite diagnosis of torticollis. The widely used term of congenital muscular torticollis resulted in morbid or mortal consequences. Moreover, some patients received vigorous physical therapy on the bases of muscular torticollis. Sadly speaking, this resulted in grave complications. Understanding the imaging phenotype and the genotype in such patients is the baseline tool for precise and proper management. The value of this paper is to sensitise physicians and orthopaedic surgeons to the necessity of comprehensive clinical and radiological phenotypic characterisations in patients with long term skeletal pathology.

Fournier's Gangrene: validation of the severity index.

INTRODUCTION: Fournier's gangrene is a serious infection and is considered a major emergency. A complete assessment of the severity factors using a severity score is essential and makes it possible to adapt the therapeutic management. AIM: Validate Fournier's Gangrene Severity Index and evaluate its benefits in the initial assessment of disease severity. METHODS: This is a retrospective, monocentric study which gathered all the cases of perineal gangrene that were managed in General Surgery Department of Habib Bougatfa Hospital in Bizerte over a period of 8 years. The primary endpoint in our study was mortality. RESULTS: Thirty-five cases of Fournier's gangrene were collected. The average age of our patients was 46 years. Mortality rate was 23%. We calculated the Fournier's Gangrene Severity Index for 22 patients. There was a significant difference in the average Fournier's Gangrene Severity Index score between the group of surviving patients (3.75) and the group of deceased patients (12.63) (p 9.5 (sensitivity 87.5%, specificity 100%), we noted that the mortality rate was significantly higher in the group with a score> 10 (100%) than in the group with a score ≤ 9 (6%) (p.

Heterogeneous clinical features in Cockayne syndrome patients and siblings carrying the same CSA mutations.

BACKGROUND: Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC6/CSB or ERCC8/CSA that participate in the transcription-coupled nucleotide excision repair (TC-NER) of UV-induced DNA damage. CS patients display a large heterogeneity of clinical symptoms and severities, the reason of which is not fully understood, and that cannot be anticipated in the diagnostic phase. In addition, little data is available for affected siblings, and this disease is largely undiagnosed in North Africa. METHODS: We report here the clinical description as well as genetic and functional characterization of eight Tunisian CS patients, including siblings. These patients, who belonged to six unrelated families, underwent complete clinical examination and biochemical analyses. Sanger sequencing was performed for the recurrent mutation in five families, and targeted gene sequencing was done for one patient of the sixth family. We also performed Recovery RNA Synthesis (RRS) to confirm the functional impairment of DNA repair in patient-derived fibroblasts. RESULTS: Six out of eight patients carried a homozygous indel mutation (c.598_600delinsAA) in exon 7 of ERCC8, and displayed a variable clinical spectrum including between siblings sharing the same mutation. The other two patients were siblings who carried a homozygous splice-site variant in ERCC8 (c.843+1G>C). This last pair presented more severe clinical manifestations, which are rarely associated with CSA mutations, leading to gastrostomy and hepatic damage. Impaired TC-NER was confirmed by RRS in six tested patients. CONCLUSIONS: This study provides the first deep characterization of case series of CS patients carrying CSA mutations in North Africa. These mutations have been described only in this region and in the Middle-East. We also provide the largest characterization of multiple unrelated patients, as well as siblings, carrying the same mutation, providing a framework for dissecting elusive genotype-phenotype correlations in CS.

Identification and Characterization of a Novel Recurrent ERCC6 Variant in Patients with a Severe Form of Cockayne Syndrome B.

Cockayne syndrome (CS) is a rare disease caused by mutations in ERCC6/CSB or ERCC8/CSA. We report here the clinical, genetic, and functional analyses of three unrelated patients mutated in ERCC6/CSB with a severe phenotype. After clinical examination, two patients were investigated via next generation sequencing, targeting seventeen Nucleotide Excision Repair (NER) genes. All three patients harbored a novel, c.3156dup, homozygous mutation located in exon 18 of ERCC6/CSB that affects the C-terminal region of the protein. Sanger sequencing confirmed the mutation and the parental segregation in the three families, and Western blots showed a lack of the full-length protein. NER functional impairment was shown by reduced recovery of RNA synthesis with proficient unscheduled DNA synthesis after UV-C radiations in patient-derived fibroblasts. Despite sharing the same mutation, the clinical spectrum was heterogeneous among the three patients, and only two patients displayed clinical photosensitivity. This novel ERCC6 variant in Tunisian patients suggests a founder effect and has implications for setting-up prenatal diagnosis/genetic counselling in North Africa, where this disease is largely undiagnosed. This study reveals one of the rare cases of CS clinical heterogeneity despite the same mutation. Moreover, the occurrence of an identical homozygous mutation, which either results in clinical photosensitivity or does not, strongly suggests that this classic CS symptom relies on multiple factors.

Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.

Infantile systemic hyalinosis: Variable grades of severity.

BACKGROUND: Infantile systemic hyalinosis (ISH) is an autosomal recessively inherited disorder. The classical natural history of the disease is characterised by hypotonia, multiple contractures, skin lesions, osteopenia, joint pain, bone fractures, persistent diarrhoea and growth deficiency. MATERIALS AND METHODS: Two children manifested the severe type of ISH underwent genotypic confirmation. In order to identify which other family members have inherited the disease. We included siblings and cousins in this study. The baseline tool to study other family subjects was based on the phenotypic characterisations of each child. RESULTS: . Two children with the severe type of ISH showed craniosynostosis (brachycephaly and scaphocephaly) associated with multiple contractures, progressive joint osteolysis ending up with multiple joint dislocations. The full exome sequencing was carried out, revealing a previously reported heterozygous nonsense mutation с.1294С>Т and a novel heterozygous non-synonymous substitution c. 58T>A in ANTRX2 gene. Three children (sibling and cousins) manifested variable clinical manifestations relevant to ISH. Specifically, asymptoamtic skin and skeletal abnormalities of hypoplastic clavicles and 'shepherd's crook' deformity and coxa vara. CONCLUSION: It is mandatory to perform extensive family pedigree search to detect asymptomatic clinical features in siblings and cousins in families with first degree related marriages. Interestingly, in the mild and the moderate types of ISH, we observed undescribed combination of asymptomatic skin and skeletal abnormalities. This is a comparative study between the severe and the mild/moderate types in a group of children from consanguineous families. Our current study extends the phenotypic characterisations of ISH.