Search

Spondyloenchondrodysplasia (SPENCD) is an immune-osseous disorder caused by biallelic variants in ACP5 gene and is less commonly associated with neurological abnormalities such as global developmental delay, spasticity and seizures. Herein, we describe five new patients from four unrelated Egyptian families with complex clinical presentations including predominant neurological presentations masking the skeletal and immunological manifestations. All our patients had spasticity with variable associations of motor and mental delay or epilepsy. All except for one patient had bilateral calcification in the basal ganglia. One patient had an associated growth hormone deficiency with fair response to growth hormone therapy (GH) where the height improved from −3.0 SD before GH therapy to −2.35 SD at presentation. Patients had different forms of immune dysregulation. All patients except for one had either cellular immunodeficiency (3 patients) or combined immunodeficiency (1 patient). Whole exome sequencing was performed and revealed four ACP5 variants: c.629C > T (p.Ser210Phe), c.526C > T (p.Arg176Ter), c.742dupC (p.Gln248ProfsTer3) and c.775G > A (p.Gly259Arg). Of them, three variants were not described before. Our study reinforces the striking phenotypic variability associated with SPENCD and expands the mutational spectrum of this rare disorder. Further, it documents the positive response to growth hormone therapy in the studied patient.

Introduction: The underlying molecular defects of congenital hydrocephalus are heterogeneous and many isolated forms of hydrocephalus remain unsolved at the molecular level. Congenital hydrocephalus in males associated with agenesis of the corpus callosum is a notable characteristic of L1CAM gene which is by far the most common genetic etiology of congenital hydrocephalus. Methods and Results: Sequencing of the L1CAM gene on 25 male patients/fetuses who had been presented with hydrocephalus revealed 6 patients and two fetuses with different hemizygous pathogenic variants. Our study identified 4 novel variants and 4 previously reported. The detection rate was 32%, and all the variants were shown to be maternally inherited. Nonsense variants were detected in 3 patients, while missense variants were detected in 2 patients. Frameshift, silent, and splicing variant, each was detected in 1 patient. The clinical manifestations of the patients are in line with those frequently observed including communicating hydrocephalus and agenesis of the corpus callosum. Moreover, rippled ventricles with subdural collection and asymmetry of ventricles after shunt operation were seen in 1 patient and 2 patients, respectively. In addition, abnormal basal ganglia were found in 4 patients which seems to be an additional distinct new finding. We also describe a patient with novel nonsense variant with the rare association of Hirschsprung’s disease. This patient displayed additionally multiple porencephalic cysts and encephalomalacia secondary to hemorrhage due to repeated infections after shunt operation. The patients with the missense variants showed long survival, while those with truncating variants showed poor prognosis. Conclusion: This report adds knowledge of novel pathogenic variants to the L1CAM variant database. Furthermore, we evaluated the clinical and imaging data of these patients.

Diabetes mellitus is a worldwide disease that requires special and continuous medical care. Many classes of oral hypoglycemic drugs are currently used; however, the treatment strategy depends on the nature of diabetes type, pharmacological properties of the used drugs in addition to the clinical characteristics of the patient. As such, in this literature review, we will shed the light on the pharmacology and analytical chemistry profile of certain oral hypoglycemic drugs specifically Dapagliflozin, Empagliflozin and Saxagliptin that got attention in the last decade. Mode of action and most of up-to-date reported methods that have been developed for determination of these important anti-diabetic drugs in their pure form, combined form with other drugs, combined form with degradation products, and in biological samples are mentioned in detail.

Mutations in the PORCN gene cause an X-linked dominant condition; focal dermal hypoplasia (FDH), characterized by atrophic skin, pigmented skin lesions in addition to several ocular and skeletal malformations. FDH is rare with around 275 cases reported so far from diverse ethnic groups. Herein, we provide a report of two new patients with FDH from Egypt. In addition to the typical clinical manifestations of the disease, infrequently reported clinical findings in the form of broad metaphysis, bilateral short broad femurs, and dermal sinus over the sacrum were seen in Patient 1 and partial fusion of labia majora, ventral hernia, and bladder extrophy were present in Patient 2. Two heterozygous protein-truncating PORCN mutations were identified in our patients, a known nonsense c.370CT p.(Arg124Ter) and a novel frameshift c.375delG p.(Ala126HisfsTer3). Segregation analyses confirmed that the two mutations were "de novo" and not inherited from any of the parents. Our study expands the clinical and mutational spectrum of focal dermal hypoplasia and emphasizes the importance of investigating the different body systems and organs for the early management of patients.

An anthelmintic, rafoxanide (RF), is frequently used in veterinary medicine to cure fascioliasis in cattle and sheep. A sensitive, quick, and selective detection of RF in its pharmaceutical preparation and in human urine was achieved through developing a new electrochemical sensor. The suggested method relied on the electro-oxidation of RF that used a modified carbon paste electrode in the presence of sodium dodecyl sulfate, which acts as an anionic surfactant. Voltammetric types were utilized in RF analysis, and these methods were cyclic voltammetry and differential pulse techniques. The suggested electro-analytical method’s validity is verified using the International Council on Harmonization (ICH/Q2) rules. The calibration curve for RF quantification was done in the concentration range from 2.9 × 10−6 to 3.1 × 10−4 M at cadmium sulfide modified carbon paste electrode. The limit of detection and the limit of quantification LOQ were found to be 6.7 × 10−7 M and 2.01 × 10−6 M, respectively. This study could be applied to the examined drug in QC-laboratory units, and also RF could be assayed in its pharmacokinetic studies.

Introduction: Pathogenic variants in the PIEZO family member 2 (PIEZO2) gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5). Out of these, MWS has a recognizable phenotype that can be discerned easily, but the distinction between GS and DA5 is less evident. Few children with pathogenic PIEZO2 variants have been reported to show posterior fossa anomalies. Methods and Results: By candidate gene targeting guided by proper clinical evaluation and neuroimaging findings, a patient with classic MWS harboring a de novo novel variant (c.8237G>A, p.W2746*) in the C-terminal region of PIEZO2 was identified. In addition, another girl with the typical clinical features of GS is also described carrying the most prevalent reported variant (c.8057G>A, p.R2686H) in PIEZO2. The brain MRI of the 2 patients showed Dandy-Walker malformation (DWM). Diffusion tensor imaging visualized anteroposterior and downward aligned thin middle cerebellar peduncle. The association of DWM with arthrogryposis in the presence of PIEZO2 variants remains quite interesting and provides more evidence that PIEZO2 plays a role in the development of hindbrain although the underlying mechanism remains unclear. Moreover, the 2 girls had distinct foot patterning in the form of shortening of the first and fifth toes. Conclusion: Phenotype analysis and a comprehensive review of the literature strongly support the previously published data and corroborate the evidence that heterozygous PIEZO2-related disorders represent a continuum with overlapping phenotypic features.

International audience; Introduction: Disorders of gonadal development represent a clinically and genetically heterogeneous group of DSD, and the etiology in many cases remains unknown, indicating that our knowledge of factors controlling sex determination is still limited. Methods: We describe a 46,XY DSD patient from Egypt. The patient was reared as female, born to consanguineous parents, and was referred to us at the age of 5 years because of ambiguous genitalia. On examination, the girl was microcephalic (head circumference –3 SD), but her height and weight were normal for her age and sex. Results: Exome sequencing identified a homozygous variant in the hedgehog acyltransferase (HHAT) gene, which encodes an enzyme that is required for multimerization and signaling potency of the hedgehog secreted proteins. The variant is a novel homozygous missense change c.1329C>A (p.N443K), located within transmembrane domain 9, which segregated with the phenotype in the family. Discussion/Conclusion: Our results expand the phenotypic spectrum associated with HHAT variants to include 46,XY gonadal dysgenesis and reinforce the role of exome sequencing in unraveling new genes that play a pivotal role in sexual development.

Background In the scenario of lung lesions, the differential diagnosis is important, since the treatment is determined by the characteristics of the lesion. The goal in the evaluation of pulmonary lesions is to distinguish malignant lesions from benign lesions in a non-invasive manner as possible. Since, CT is not sufficient to accurately distinguish malignant nodules from benign nodules and patients with benign nodules might undergo invasive diagnostic methods, such as lung biopsy or video-assisted thoracoscopic surgery, to rule out a malignancy. Now, MRI performed by using diffusion-weighted (DW) can offer both qualitative and quantitative information that can be helpful for tumour assessment. Moreover, lesion‐to‐spinal cord signal intensity ratio (LSR) has also been shown to be useful for the differentiation of lung lesions. Quantitative tumour assessment is possible by the calculation of ADC. Results A total of 30 patients were eligible for inclusion in our final analysis; with male/female case number about 10/20 (33.3%/ 66.7%) and age range from 20 to 74 (46.8 ± 14.9) were subjected to MRI study and MRI diffusion. Sensitivity analysis showed that ADC mean, and ADC min value can significantly predict malignant lung lesions using cutoff point p values 0.001, and 0.005 respectively. SI lesion can significantly predict malignant lung lesions using cutoff point > 502.8, with sensitivity 92.9% and specificity 68.7%, AUC 89.3% and p value 0.0001. Lesion-to-spinal cord signal intensity ratio (LSR) can significantly predict malignant lung lesions using cutoff point > 1.3, with sensitivity 85.7% and specificity 75%, AUC 79.7% and p value 0.006. Conclusions This study confirmed that the DWI combined with ADC value and LSR is effective and valuable tool in differentiation of pulmonary lesions whether benign or malignant which is considered to be noninvasive alternative tool for the characterization of pulmonary lesions. We recommend before invasive intervention to perform diffusion MRI and LSR as and important aid for proper diagnosis.

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

Turkevich gold nanoparticles are the original nanoparticles that have been modified over time. Its combination with targeting medications such as alendronate, memantine, and tobramycin will provide additional benefits intargeting specific areas in the bone, brain, and microorganisms, respectively.Hence, The reactivity and stability of nanoparticles with various drugconcentrations (milli-,micro-, and nano-levels) have been studied. Withalendronate, the absorbance spectra of nanoparticles at λmax 520 nm werealways stable and no redshifts occurred. In contrast, the spectra with memantineand tobramycin were stable at the nano-level and redshifts occurred at the milli-& micro- levels. HRTEM and DLS revealed that the core diameter was relativelystable in all cases, whereas the hydrodynamic diameter & zeta potential variedwith varying drug concentrations. Increasing concentration increasedhydrodynamic diameter slightly with memantine (from 64.99 to 98.41 nm),dramatically with tobramycin (from 135.3 to 332.16 nm), and almost negligiblywith alendronate (from 52.08 to 58.94 nm ). Zeta Potential, conversely, isreduced as concentration increases. Memantine had the greatest reduction innegativity, followed by tobramycin, but alendronate had a slight increase innegativity. Benefits from this research would be in targeted drug delivery, wherestability and reactivity of gold nanoparticles are critical.

Papillon Lefevre syndrome (PLS) is an autosomal recessive disorder that results from a mutated gene that encodes a lysosomal peptidase known as cathepsin C (CTSC). The clinical presentation of PLS involves mainly palmoplantar keratosis and periodontitis with a variable degree of severity.and methods: Our study included ten patients with a broad spectrum of palmoplantar keratosis and periodontitis severity. CTSC variants were detected by Sanger sequencing. CTSC protein secreted in urine was detected by western blotting.Five patients have missense variants, Four have nonsense variants, and one has splice variants in CTSC. The activation products of cathepsin C protein (Heavy and light chains) were absent in all patients' urine samples except one with a significantly reduced level compared to the controls. The dimeric form of CTSC protein was found in all the studied cases. The monomeric form was found in five cases. The products of proteolytic activation of CTSC by other cathepsins (L and S) were found in the urine samples of five of the patients. Each patient had a characteristic pattern of accumulated CTSC protein maturation/activation substrates, intermediates, and products. 40% of the patients had the activation products of other lysosomal cathepsins.Urinary CTSC in PLS patients could be used as a diagnostic biomarker for the biochemical screening of the disease. Different variants in CTSC result in different profiles of CTSC secreted in the urine of PLS patients. The profiles of secreted CTSC in urine could be correlated to the severity of palmoplantar keratosis.

Wollastonite with/without maghemite [(Fe2O3), 0, 3 and 10 wt%] was prepared by facile wet precipitation method. Effect of Fe2O3 presence in the obtained nano-ceramics on physical structure, morphology, size and the mechanical features was evaluated using X-ray diffraction, transmission electron microscope, and universal testing machine. Moreover, the in vitro biomineralization was examined using simulated body fluid (SBF) by means of scanning electron microscope/energy dispersive X-ray, Fourier transform infrared, and inductively coupled plasma. An in vivo study was conducted on 24 adult male mongrel dogs to test the biosafety of fabricated samples in the reconstruction of experimentally induced mandibular bone defects. Bone density was measured through cone beam computed tomography analysis conducted at 1 and 3 months following surgery. Wollastonite was the main phase in all the prepared samples however little maghemite was developed in Fe-containing samples. No remarkable changes were recognized for physical structure of obtained microcrystalline structures, however, a decrease in particle size was noted in the existence of Fe2O3 (10-15 nm) when compared to the pure wollastonite (30-50 nm). Mechanical features were dependent on the included Fe2O3 concentration within the wollastonite ceramic matrix. The degree of biomineralization of the samples immersed in SBF was elevated with the increase in Fe2O3 percentage. Clinically, the reconstruction of bone defects was uneventful without any adverse toxic effect. Bone density was significantly increased at 1 and 3 months (p

Micro and Martsolf syndromes are rare clinically and genetically overlapping disorders caused by mutations in RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20 genes. We describe 34 new patients, 27 with Micro and 7 with Martsolf. Patients presented with the characteristic clinical manifestations of the two syndromes including postnatal microcephaly, congenital cataracts, microphthalmia, optic atrophy, spasticity and intellectual disability. Brain imaging showed in the majority of cases polymicrogyria, thin corpus callosum, cortical atrophy, and white matter dysmyelination. Unusual additional findings were pectus excavatum (4 patients), pectus carinatum (3 patients), congenital heart disease (3 patients) and bilateral calcification in basal ganglia (1 patient). Mutational analysis of RAB3GAP1 and RAB3GAP2 revealed 21 mutations including 14 novel variants. RAB3GAP1 mutations were identified in 22 patients with Micro including a deletion of the entire gene in one patient. On the other hand, RAB3GAP2 mutations were identified in two patients with Micro and all Martsolf patients. Moreover, exome sequencing unraveled a TBC1D20 mutation in an additional family with Micro syndrome. Our results expand the phenotypic and mutational spectrum associated with Micro and Martsolf syndromes. Due to the overlapped severities and genetic basis of both syndromes, we suggest to be comprehended as one entity "Micro/Martsolf spectrum" or "RAB18 deficiency". This article is protected by copyright. All rights reserved.

The alpha angle is routinely used for the diagnosis and quantitative description of the Cam deformity of the hip. However, a reliable identification of the femoral neck axis as its reference line can be difficult. Moreover, most cam resections include a reduction of the femoral neck diameter with an automatic posteromedial angulation of the femoral neck axis. In consequence, the reference axes for the pre- and postoperative alpha angles are different, and a comparison of both angles underlies a systematic error to relatively higher postoperative alpha angles. In order to avoid this systemic error, we propose the hip asphericity (HA) angle with a reference axis independent of the amount of bony resection. Two retrospective groups were formed, a ‘femoroacetabular impingement (FAI) group’ that had hip arthroscopy for cam resection and a ‘Control group’ without cam deformity. The alpha and HA angles were measured by three examiners. The measurements were repeated 1 month later. In the FAI group, offset correction was calculated using both angles. Statistically significant differences for both the alpha and the HA angles were found between the control and the preoperative FAI group as well as between the preoperative and postoperative FAI groups. The HA angle-correction by a mean of 27.5° was significantly higher in comparison to the alpha angle correction by a mean of 25.4°. The intertester and intratester reliability of both angles were not significantly different. The HA angle is a new and reliable radiographic parameter for measuring cam deformity and proves superior in measuring cam correction.

Purpose The aim of this study was to test the hypothesis that the dose of estrogen replacement therapy may have an influence on the clinical, radiographic, and histopathologic changes within the temporomandibular joint (TMJ). Materials and Methods A prospective experimental study was conducted in 12 mature ovariectomized dogs. Dogs were randomly allocated into 1 of 4 groups (OVX-E0, dogs that did not receive any estrogen replacement therapy; OVX-E0.5, dogs that received 0.15 mg/kg of estradiol; OVX-E1, dogs that received 0.3 mg/kg of estradiol; and OVX-E2, dogs that received 0.6 mg/kg of estradiol); dogs were evaluated clinically for 12 weeks; and contact radiographic and histopathologic examinations of the TMJ were performed just after euthanasia. Results Radiographic examination of the TMJ in the OVX-E0 group showed narrowing of the joint space with marginal osteophyte formation along the mandibular condyle. The OVX-E0.5 group showed mild widening of the joint space with no remarkable changes within the mandibular fossa or condyle. The OVX-E1 group was free of radiographic changes within the TMJ. High doses of estrogen in the OVX-E2 group showed marked flattening of the mandibular condyle and fossa with sclerosis of the subchondral bone. Histopathologic sections in the OVX-E0 group showed thin compact bone with scanty, less organized lacunae. The OVX-E0.5 group showed compact bone of medium thickness with large osteons and disorganized lacunae. The OVX-E1 group showed thick compact bone with reduced intertubercular spaces and organized lacunae. The OVX-E2 group showed thin bone with reduced trabecular and increased intertrabecular thickness. The collagen content did not change significantly among the 4 groups, whereas its quality changed significantly (P Conclusions Estrogen dosage is potentially a key regulator of bone metabolism within the TMJ. Estrogen replacement therapy exhibited an inverted U–shaped beneficial effect. Estrogen depletion as well as high doses of estrogen resulted in clinical, radiographic, and histopathologic changes within the TMJ. Estrogen replacement therapy should be prescribed at the optimum dose when indicated as hormonal replacement therapy.

Studies and statistics emphasize that the temperatures and climate change of the atmosphere have recorded a change between high temperature and humidity over the past 100 years. It is expected by the end of the current century, that the global temperature will rise significantly, if the rates of change and greenhouse gas emissions in the atmosphere multiply, especially carbon dioxide; as stated in the report of the United Nations Intergovernmental Panel on Climate Change (IPCC). Undoubtedly, the climate change shall have a negative and clear impact on the internal and external environment in terms of high temperature due to global warming and the increase in the percentage of humidity and acid rain which affect the health and psychology of inhabitants of the environment, as well as the components of the external environment such as plants, birds and living beings. Therefore, the research aims to determine the aforementioned impacts and results thereof, and observe the resulting environmental changes and impacts thereof on users. With the adoption of the state and its concern to achieve the requirements of quality of life and thus, they are achieved through raising the environmental standard of living for users, and by determining the impact of climate changes expected on the internal and external environment of buildings to find alternatives and architectural solutions to deal with such impacts and create an environmental balance and return to the nature created by God Almighty and achieve thermal comfort which meets their needs and achieve quality of life. The study shall be tackled through an inductive approach to observe such climate changes and determine the places of direct impact on the internal and external buildings through the analytical approach leading to the findings of the aforementioned study. Accordingly, the architectural and urban alternatives and treatments shall be chosen through the applied approach to a study sample leading to observing the final results of the research and suggesting directions that would achieve the user's requirements of quality of life in the architectural and urban environment. تؤکد الدراسات والإحصائيات أن درجات الحرارة والتغير المناخى للغلاف الجوى قد سجلت خلال المائة عام الماضية تغيرا ما بين ارتفاع درجة الحرارة ونسبة الرطوبة، ومن المتوقع مع نهاية القرن الحالى أن ترتفع درجة الحرارة فى العالم ارتفاعا ملحوظا، إذا ما تضاعفت معدلات التغير وانبعاث الغازات الدفيئة فى الغلاف الجوى وبخاصة ثانى أکسيد الکربون، وذلک کما جاء فى تقرير اللجنة الحکومية الدولية المعنية بالمناخ التابعة للأمم المتحدة. ومما لا شک فيه أن تغير المناخ سيؤثر تأثيرا سلبيا وواضحا على فراغ البيئة الداخلية والخارجية من حيث ارتفاع درجة الحرارة نتيجة للاحتباس الحرارى وزيادة نسبة الرطوبة والأمطار الحامضية وغيرها مما يؤثر على صحة ونفسية المستخدمين للفراغ وکذلک عناصر البيئة الخارجية من نباتات وطيور وکائنات حية وخضراء، لذا يهدف البحث إلى تحديد تلک المؤثرات ونتائجها ورصد التغيرات البيئية الناتجة ومدى تأثيرها على المستخدمين. ومع تبنى الدولة واهتمامها بتحقيق متطلبات جودة الحياة وبالتالى يتحقق من خلال رفع مستوى المعيشة البيئية للمستخدمين، ومن خلال تحديد أثر المتغيرات المناخية المتوقعة على بيئة المبانى الداخلية والخارجية، لإيجاد بدائل وحلول معمارية لمعالجة تلک التأثيرات وإحداث اتزان بيئى والعودة إلى الطبيعة التى خلقها الله - سبحانه وتعالى – وتحقيق راحة حرارية تلبى احتياجاتهم وتحقيق جودة حياة. وسيتم تناول الدراسة من خلال المنهج الإستقرائى لرصد تلک التغيرات المناخية وتحديد مواضع التأثير المباشر على بيئة المبانى الداخلية والخارجية من خلال المنهج التحليلى وصولا إلى استخلاص نتائج لتلک الدراسة، وعليه سيتم اختيار البدائل والمعالجات المعمارية والعمرانية من خلال اتباع المنهج التطبيقى على عينة دراسة وصولا إلى رصد النتائج النهائية للبحث واقتراح توجيهات التى من شأنها تحقق متطلبات المستخدم من جودة حياة فى البيئة المعمارية والعمرانية.

A fast, green, sensitive, and accurate analytical method using high-performance liquid chromatography couple with fluorescence detection was established and validated for the simultaneous determination of amlodipine besylate and celecoxib in their recently approved fixed-dose combination tablets (1:20). Separation of the two drugs was achieved on C18 reversed-phase column (Thermo ODS Hypersil, 4.6 × 250 mm, particle size 5 µm) using acetonitrile:potassium phosphate buffer (50 mM; pH 5.5, 60:40 v/v) as a mobile phase at 40°C, which eluted at a rate of 1 mL/min. Detection was carried out with excitation and emission wavelengths of 360 and 446 nm for amlodipine and 265 and 359 nm for celecoxib, respectively. The method was linear over a concentration range of 0.05-2 and 0.05-10 µg/mL and limit of detection reached to 0.017 and 0.0167 µg/mL for amlodipine and celecoxib, respectively. The developed method was successfully applied to assess the cited drugs in their newly FDA approved fixed-dose combination tablet dosage form. Furthermore, the method was found to be sensitive and eco-friendly green alternative to the reported methods as it was evaluated according to the green analytical procedure index tool guidelines and analytical Eco-Scale.

KBG syndrome is an intellectual disability (ID) associated with multiple congenital anomalies in which the macrodontia could be the clue for the diagnosis. It is caused either by heterozygous variant in ANKRD11 gene or 16q24.3 microdeletions that involve the ANKRD11 gene. Here, we report on two unrelated male patients who presented with ID, short stature, webbing of neck, and cryptorchidism. Noonan syndrome was suspected first but the presence of macrodontia in both patients pointed to KBG syndrome which was confirmed thereafter by the identification of a novel pathogenic variant in ANKRD11 gene, c.5488G>T (p.E1830*). Macrodontia was noticed in all the deciduous anterior teeth in Patient 1. This observation was reported previously in few patients, but it seems to be a common feature that could be misdiagnosed as premature eruption of teeth. Therefore, our results confirm that maxillary permanent central incisors may not be the only teeth affected in KBG but also all the deciduous teeth. Interestingly, desquamative gingivitis was additionally noted in Patient 1, which has not been reported previously, however; it could be a coincidental finding. To the best of our knowledge, this is the first report from Egypt.

Turkevich Gold nanoparticles are the original nanoparticles that have been modified over time. Combining nanoparticles with targeting medications such as alendronate, memantine, and tobramycin will provide additional benefits in targeting specific areas in the bone, brain, and microorganisms, respectively. The reactivity and stability of nanoparticles in the presence of various drug concentrations (micro-, nano-, and milli-levels) have been studied. The absorbance spectra of nanoparticles at λmax 520 nm were always stable with alendronate, whereas with memantine and tobramycin, the spectra were unchanged (no color change) in the nano- level over twenty minutes and red shifts (color change) occurred in the micro-level. High Resolution Transmission Electron Microscopy (HRTEM) and • Dynamic light scattering (DLS) revealed that the core diameter was relatively stable in all cases, whereas the hydrodynamic diameter and zeta potential varied with drug concentration. Increasing concentration increased hydrodynamic diameter slightly with memantine (from 64.99 to 98.41 nm), dramatically with tobramycin (from 135.3 to 332.16 nm), and almost negligibly with alendronate (from 52.08 to 58.94 nm). Zeta potential, conversely, is reduced as concentration increases. Memantine had the greatest reduction in negativity, followed by tobramycin, but alendronate had a slight increase in negativity. This research would be useful for the application of gold nanoparticles in targeted drug delivery, where the stability and reactivity of gold nanoparticles are critical.

Developmental brain malformations are rare but are increasingly reported features of BICD2-related disorders. Here, we report a 2-year old boy with microcephaly, profound delay and partial seizures. His brain MRI showed lissencephaly, hypogenesis of corpus callosum, dysplastic hipocampus and cerebellar hypoplasia. Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the BICD2 gene, c.229 C > T p.(Gln77Ter). This is the first report of lissencephaly and cerebellar hypoplasia seen in a patient with homozygous loss-of-function variant in BICD2 that recapitulated the animal model. Our report supports that BICD2 should be considered in the differential diagnosis for patients with lissencephaly and cerebellar hypoplasia Additional clinical features of BICD2 are likely to emerge with the identification of additional patients.

PPFIBP1 encodes for the liprin-β1 protein which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 14 individuals from 10 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy and progressive microcephaly. Further common clinical findings included muscular hypertonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired hearing and vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM-domain region that is essential for protein-protein interaction. For further insight in the effects of PPFIBP1 loss-of-function, we performed automated behavioural phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model which revealed defects in spontaneous and light-induced behaviour and confirmed resistance to the acetylcholinesterase inhibitor aldicarb suggesting a defect in the neuronal presynaptic zone. In conclusion, we present bi-allelic loss-of-function variants in PPFIBP1 as a novel cause of an autosomal recessive neurodevelopmental disorder.

Bruck Syndrome (BS) is a very rare disorder characterized by osteogenesis imperfecta (OI) associated with congenital contractures and is caused by mutations in FKBP10 or PLOD2 genes. Herein, we describe 13 patients from 9 unrelated Egyptian families with BS. All patients had white sclerae, recurrent fractures, kyphoscoliosis and osteoporosis with variable degrees of severity. Large joint contractures were seen in 11 patients, one patient had contractures of small interphalangeal joints, and one patient had no contractures. Unusual findings noted in individual patients included microcephaly, dental malocclusion, enamel hypoplasia, unilateral congenital dislocation of knee joint, prominent tailbone, and myopathy. Nine different variants were identified in FKBP10 and PLOD2 including five novel ones. FKBP10 variants were found in six families (67%) while PLOD2 variants were identified in three families (33%). The four families, with two affected sibs each, showed inter- and intrafamilial phenotypic variability. In conclusion, we report five novel variants in FKBP10 and PLOD2 thus, expanding the mutational spectrum of BS. In addition, our results expand the phenotypic spectrum, describe newly associated orodental findings, and further illustrate the phenotypic overlap between OI and Bruck syndrome supporting the suggestion of considering BS as a variant of OI rather than a separate entity.

A novel optical nano-sensor for the detection of pregabalin (PG) in its pharmaceutical (Lyrica®) capsules and biological samples was reported. For the fabrication of highly fluorescent carbon quantum dots (CQDts), a simple green hydrothermal approach was described, and ascorbic acid (AA) was used as a carbon source. The obtained CQDts were confirmed by spectroscopic characterization such as transmission electron microscopy (TEM) and Fourier-transform infrared (FTIR) spectra. The synthesized CQDts were capped by alcohol to form yellow emitters, showing strong fluorescent emission at 524 nm, and excitation at 356 nm. The method is based on fluorescence quenching of CQDts in the presence of PG. The proposed analytical method was validated according to ICH guidelines. PG was successively assayed in the concentration range of 4.0 to 100 μg/ml). The detection and quantitation limits were 1.12 and 3.39 μg/ml, respectively. The proposed method could be used in both quality control and pharmacokinetic research for the studied drug.

This study describes the clinical, radiological, and molecular data of four new patients with osteoporosis-pseudoglioma syndrome and assesses their response to bisphosphonate therapy.Osteoporosis-pseudoglioma syndrome (OPPG) is a very rare disorder characterized mainly by severe juvenile osteoporosis and congenital blindness. OPPG is caused by biallelic mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5).We present the clinical, radiological, and molecular findings of four new patients with OPPG from Egypt. We also assessed patients' response to oral and intravenous bisphosphonate therapy.All patients had reduced bone mineral density (BMD) with variable number of fractures per year, in addition to bone abnormalities and the characteristic eye phenotype associated with OPPG. Mutation analyses of LRP5 gene revealed three different homozygous variants including two novel ones, c.7delG (p.A3Qfs*80) and c.3280G A (p.E1094K). The c.3280G A (p.E1094K) was recurrent in two unrelated patients who shared a unique haplotype suggesting a possible founder effect. The use of bisphosphonate therapy was beneficial; however, intravenous bisphosphonate administration led to a more favorable response.Our study described the phenotypic and genetic features of four patients with OPPG and identified two new LRP5 variants, thus expanding the mutational spectrum of OPPG. In addition, our study reinforces the efficiency of using intravenous bisphosphonates in the management of patients with OPPG.