Whole-exome sequencing of T- B+ severe combined immunodeficiency in Egyptian infants, JAK3 predominance and novel variants.

Severe combined immunodeficiency (SCID) is fatal if not treated with immune reconstitution. In Egypt, T- B+ SCID accounts for 38·5% of SCID diagnoses. An accurate genetic diagnosis is essential for choosing appropriate treatment modalities and for offering genetic counseling to the patient's family. The objectives of this study were to describe the clinical, immunological and molecular characteristics of a cohort of twenty Egyptian patients with T- B+ SCID. The initial diagnosis (based on clinical features and flow cytometry) was followed by molecular investigation (whole-exome sequencing). All patients had the classic clinical picture for SCID, including failure to thrive (n = 20), oral candidiasis (n = 17), persistent diarrhea (n = 14), pneumonia (n = 13), napkin dermatitis (n = 10), skin rash (n = 7), otitis media (n = 3) and meningitis (n = 2). The onset of manifestations was at the age of 2·4 ± 1·6 months and diagnosis at the age of 6·7 ± ·5 months, giving a diagnostic delay of 4·3 months. JAK3 gene variants were most frequent (n = 12) with three novel variants identified, followed by IL2Rγ variants (n = 6) with two novel variants. IL7Rα and CD3ε variants were found once, with a novel variant each. T- B+ NK- SCID accounted for approximately 90% of the Egyptian patients with T- B+ SCID. Of these T- B+ NK- SCID cases, 60% were autosomal recessive syndromes caused by JAK3 mutations and 30% were X-linked syndromes. It might be useful to sequence the JAK3 gene (i.e. targeted Sanger sequencing) in all T- B+ SCID patients, especially after X-linked SCID has been ruled out. Hence, no more than 10% of T- B+ SCID patients might require next-generation for a molecular diagnosis.

Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population.

Mutations affecting recombination activation genes RAG1 and RAG2 are associated with variable phenotypes, depending on the residual recombinase activity. The aim of this study is to describe a variety of clinical phenotypes in RAG-deficient patients from the highly consanguineous Egyptian population. Thirty-one patients with RAG mutations (from 28 families) were included from 2013 to 2017. On the basis of clinical, immunological and genetic data, patients were subdivided into three groups; classical T- B- severe combined immunodeficiency (SCID), Omenn syndrome (OS) and atypical SCID. Nineteen patients presented with typical T- B- SCID; among these, five patients carried a homozygous RAG2 mutation G35V and five others carried two homozygous RAG2 mutations (T215I and R229Q) that were detected together. Four novel mutations were reported in the T- B- SCID group; three in RAG1 (A565P, N591Pfs*14 and K621E) and one in RAG2 (F29S). Seven patients presented with OS and a novel RAG2 mutation (C419W) was documented in one patient. The atypical SCID group comprised five patients. Two had normal B cell counts; one had a previously undescribed RAG2 mutation (V327D). The other three patients presented with autoimmune cytopaenias and features of combined immunodeficiency and were diagnosed at a relatively late age and with a substantial diagnostic delay; one patient had a novel RAG1 mutation (C335R). PID disorders are frequent among Egyptian children because of the high consanguinity. RAG mutations stand behind several variable phenotypes, including classical SCID, OS, atypical SCID with autoimmunity and T- B+ CID.

Chronic granulomatous disease: Review of a cohort of Egyptian patients.

BACKGROUND: Chronic granulomatous disease (CGD) is an inherited disease that results from a defect in the phagocytic cells of the immune system. It is caused by defects in one of the major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The clinical presentations of CGD patients are heterogeneous. OBJECTIVES: This is the first report from Egypt discussing clinical and laboratory data of twenty-nine patients (from 26 families) with CGD from a single tertiary referral centre. RESULTS: There were twenty male and nine female patients. The consanguinity rate was 76% (19/25). Their age of diagnosis ranged from 2 to 168 months with a mean of 52.8 months ± 49.6 SD. The most common manifestations were abscesses in 79.3% (deep organ abscesses in 37.9% of patients), followed by pneumonia in 75.8% and gastrointestinal symptoms in 27.5%. Rare but fatal complications were also reported among patients as one patient developed haemophagocytic lymphohistiocytosis (HLH) syndrome. Although X linked-CGD universally constitutes the most common pattern of inheritance; only 6 of our patients 6/25 (24%) belonged to this group with a Stimulation Index (SI) of 1-5, and confirmed by carrier pattern of their mothers. Mothers were not available for testing in four male children. Nineteen patients (76%) had autosomal recessive patterns; ten males and nine females patients based on having abnormal SI, positive history of consanguinity and their mothers showing normal SI. CONCLUSION: Increasing the awareness of physicians about symptoms of CGD may lead to earlier diagnosis of the disease, thus enhancing proper management and better quality of life.

Preclinical Bench Testing on a Novel Posterior Dynamic Deformity Correction Device for Scoliosis.

STUDY DESIGN: Biomechanical test. OBJECTIVE: To summarize the preclinical tests performed to assess the durability of a novel fusionless dynamic device for the treatment of adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: The minimal invasive deformity correction (MID-C) system is a distractible posterior dynamic deformity correction device designed to reduce scoliosis for AIS patients, to maintain curve correction, and to preserve spinal motion. To overcome the challenges of wear and fatigue of this procedure, the system has two unique features: polyaxial joints at the rod-screw interface and a ceramic coating of the moving parts. METHODS: Five biomechanical tests were performed: Static compression to failure, fatigue loading per ASTM F 1717 with 5.5-mm screws for 10 million cycles (MC) at 5 Hz, wear assessment, wear test of the polyaxial joint under 100 N load for 10 MC, and wear particle implantation in rabbits. RESULTS: The system failed through buckling of the rod with loads over 3000 N (400% of human body weight). Dynamically, the system maintained 700 N for 10 MC with 5.5 mm screws. The maximum total steady-state wear rate was 0.074 mg/MC (0.03 per polyaxial joint and 0.014 mg/MC for the ratchet mechanism). Histologic evaluation of the particle injection sites indicated no difference in the local tissue response between the control and test articles. At 3 and 6 months postinjection, there were neither adverse local effects nor systemic effects observed. CONCLUSIONS: The unique design features of the MID-C system, based on polyaxial joints and ceramic coating, resulted in favorable static, fatigue, and wear resistance properties. Wear properties were superior to those published for artificial spinal discs. Long-term outcomes from clinical use will be required to correlate these bench tests to the in vivo reality of clinical use. LEVEL OF EVIDENCE: Level V.

Rehabilitation of tendon injuries in sport.

Clinicians are faced with a growing number of athletes with injured tendons. Treatment of both acute and chronic injuries has proven to be quite complex. It is difficult to maintain the balance between resting the injured tendon and preventing atrophy of the surrounding muscles and joints. Questions also arise as to when the tendon should be strengthened and when the athlete is ready to return to full activity in sport. Through an awareness of the structural and mechanical properties of the tendon, an exercise programme for the rehabilitation of tendon injuries has been developed. It is recommended that this programme be used in combination with ice and other physical modalities. This approach will resolve most tendon injuries within 6 weeks of its implementation. The use of anti-inflammatory medications and surgery can only be recommended in select situations where more conservative measures are inadequate.

Chronic granulomatous disease: review of a cohort of egyptian patients

BACKGROUND: Chronic granulomatous disease (CGD) is an inherited disease that results from a defect in the phagocytic cells of the immune system. It is caused by defects in one of the major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The clinical presentations of CGD patients are heterogeneous. OBJECTIVES: This is the first report from Egypt discussing clinical and laboratory data of twenty-nine patients (from 26 families) with CGD from a single tertiary referral centre. RESULTS: There were twenty male and nine female patients. The consanguinity rate was 76% (19/25). Their age of diagnosis ranged from 2 to 168 months with a mean of 52.8 months ± 49.6 SD. The most common manifestations were abscesses in 79.3% (deep organ abscesses in 37.9% of patients), followed by pneumonia in 75.8% and gastrointestinal symptoms in 27.5%. Rare but fatal complications were also reported among patients as one patient developed haemophagocytic lymphohistiocytosis (HLH) syndrome. Although X linked-CGD universally constitutes the most common pattern of inheritance; only 6 of our patients 6/25 (24%) belonged to this group with a Stimulation Index (SI) of 1-5, and confirmed by carrier pattern of their mothers. Mothers were not available for testing in four male children. Nineteen patients (76%) had autosomal recessive patterns; ten males and nine females patients based on having abnormal SI, positive history of consanguinity and their mothers showing normal SI. CONCLUSION: Increasing the awareness of physicians about symptoms of CGD may lead to earlier diagnosis of the disease, thus enhancing proper management and better quality of life

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Occlusion and stability of synthetic femoral canal plugs used in cemented hip arthroplasty.

The occlusion and stability of five synthetic plugs used to restrict the femoral canal prior to cemented arthroplasty was assessed. A model was employed consisting of a hollow wooden dowel to simulate the canal, with adapters fixed to both ends to accommodate cement insertion and pressurization, and to produce a closed distal cavity. Three different canal diameters within the range accommodated by the plug selected were employed to assess insertion force, distal pressure during both insertion and pressurization of acrylic cement, and plug migration and leakage for each device. There was a wide variation among plugs in the magnitudes of the force and distal pressure upon plug insertion. During cement pressurization, cement leakage and/or plug migration was noted in all trials, and either of these events resulted in pressure rises in the distal cavity. Most notably, differences of only 0.5 mm in the diameter of the canal resulted in marked changes in the occlusion and stability achieved. It is concluded that for the range of canal sizes anticipated intraoperatively, these synthetic plugs appear deficient to varying extents in their ability to occlude or remain stable in the intramedullary canal.