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Current Opinion in Genetics &... Jun 2021The 16p11.2 BP4 and BP5 region, is a recurrent ∼600kb copy number variant (CNV), and deletions are one of the most frequent etiologies of neurodevelopmental disorders... (Review)
Review
The 16p11.2 BP4 and BP5 region, is a recurrent ∼600kb copy number variant (CNV), and deletions are one of the most frequent etiologies of neurodevelopmental disorders and autism spectrum disorder with an incidence of approximately 1/2000. Deletion carriers have delays in early neurodevelopment that most specifically impair speech, phonology and language in 70%. Intelligence quotient is shifted 1.8 standard deviations lower than family controls without the deletion. Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%). Unprovoked seizures are common (24%) and readily treated and resolve with age in many. Obesity evolves throughout childhood and by adulthood 75% are obese. Congenital anomalies are more common than the general population. The deletion is associated with an increase in brain volumes across all areas of the brain, changes in the white matter microstructural properties, and early electrophysiological cortical responses from auditory cortex. Studies of genetically defined conditions, particularly CNVs that are not associated with profound disabilities, provide homogeneity to study genetic impact on brain development, structure, and function to better understand complex neurobehavioral phenotypes such as autism.
Topics: Autistic Disorder; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 16; DNA Copy Number Variations; Gene Deletion; Genetic Association Studies; Humans; Intellectual Disability; Language Development Disorders; Neurodevelopmental Disorders; Neuroimaging; Obesity; Seizures; White Matter
PubMed: 33667823
DOI: 10.1016/j.gde.2021.01.011 -
Orphanet Journal of Rare Diseases Feb 2021PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR...
BACKGROUND
PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods.
RESULTS
Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported.
CONCLUSION
We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).
Topics: Aminopyridines; Child; Class I Phosphatidylinositol 3-Kinases; Humans; Imidazoles; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Quality of Life
PubMed: 33639990
DOI: 10.1186/s13023-021-01745-0 -
JAMA Feb 2021Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Coronavirus disease 2019 (COVID-19) continues to spread rapidly worldwide. Neutralizing antibodies are a potential treatment for COVID-19.
OBJECTIVE
To determine the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in mild to moderate COVID-19.
DESIGN, SETTING, AND PARTICIPANTS
The BLAZE-1 study is a randomized phase 2/3 trial at 49 US centers including ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms. Patients who received bamlanivimab monotherapy or placebo were enrolled first (June 17-August 21, 2020) followed by patients who received bamlanivimab and etesevimab or placebo (August 22-September 3). These are the final analyses and represent findings through October 6, 2020.
INTERVENTIONS
Patients were randomized to receive a single infusion of bamlanivimab (700 mg [n = 101], 2800 mg [n = 107], or 7000 mg [n = 101]), the combination treatment (2800 mg of bamlanivimab and 2800 mg of etesevimab [n = 112]), or placebo (n = 156).
MAIN OUTCOMES AND MEASURES
The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated with comparisons between each treatment group and placebo, and included 3 other measures of viral load, 5 on symptoms, and 1 measure of clinical outcome (the proportion of patients with a COVID-19-related hospitalization, an emergency department [ED] visit, or death at day 29).
RESULTS
Among the 577 patients who were randomized and received an infusion (mean age, 44.7 [SD, 15.7] years; 315 [54.6%] women), 533 (92.4%) completed the efficacy evaluation period (day 29). The change in log viral load from baseline at day 11 was -3.72 for 700 mg, -4.08 for 2800 mg, -3.49 for 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Compared with placebo, the differences in the change in log viral load at day 11 were 0.09 (95% CI, -0.35 to 0.52; P = .69) for 700 mg, -0.27 (95% CI, -0.71 to 0.16; P = .21) for 2800 mg, 0.31 (95% CI, -0.13 to 0.76; P = .16) for 7000 mg, and -0.57 (95% CI, -1.00 to -0.14; P = .01) for combination treatment. Among the secondary outcome measures, differences between each treatment group vs the placebo group were statistically significant for 10 of 84 end points. The proportion of patients with COVID-19-related hospitalizations or ED visits was 5.8% (9 events) for placebo, 1.0% (1 event) for 700 mg, 1.9% (2 events) for 2800 mg, 2.0% (2 events) for 7000 mg, and 0.9% (1 event) for combination treatment. Immediate hypersensitivity reactions were reported in 9 patients (6 bamlanivimab, 2 combination treatment, and 1 placebo). No deaths occurred during the study treatment.
CONCLUSIONS AND RELEVANCE
Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04427501.
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Antiviral Agents; COVID-19; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Hospitalization; Humans; Infusions, Intravenous; Male; Middle Aged; SARS-CoV-2; Severity of Illness Index; Viral Load; COVID-19 Drug Treatment
PubMed: 33475701
DOI: 10.1001/jama.2021.0202 -
Frontiers in Pediatrics 2020[This corrects the article DOI: 10.3389/fped.2020.574857.].
[This corrects the article DOI: 10.3389/fped.2020.574857.].
PubMed: 33425822
DOI: 10.3389/fped.2020.624141 -
Saudi Medical Journal Jan 2021Proteus syndrome (PS) is a rare overgrowth disorder that presents with asymmetrical growth of the bone and fat tissues following a mosaic pattern mutation. The estimated...
Proteus syndrome (PS) is a rare overgrowth disorder that presents with asymmetrical growth of the bone and fat tissues following a mosaic pattern mutation. The estimated worldwide incidence is approximately one in one million live births. Proteus syndrome causes disfigurement and psychological impact through its effects on somatic tissue. Due to its rarity and diversity of tissues involved, it represents a significant challenge to caregivers and multidisciplinary medical teams. Here, we report a Saudi girl, with a large left cervical mass discovered antenatally. This mass was identified as a growing cystic hygroma, and she had features of overgrowth and hemangiomas. Whole exome sequencing was negative from the blood lymphocytes and affected tissue sample. However, deletion duplication analysis from tissue shows a novel mosaic somatic mutation of the AKT1 gene. Somatic mutation remains an obstacle, and the geneticist has an essential role in its management, providing an established genetic diagnosis, prognosis, and family counselling.
Topics: Fatal Outcome; Female; Gene Duplication; Humans; Hypoxia, Brain; Infant, Newborn; Magnetic Resonance Imaging; Proteus Syndrome; Proto-Oncogene Proteins c-akt; Radiography; Sclerotherapy; Tracheostomy
PubMed: 33399177
DOI: 10.15537/smj.2021.1.25618 -
Frontiers in Pediatrics 2020Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in growth of tissue (bone, muscle, connective tissue, vasculature, etc.) in any region of... (Review)
Review
Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in growth of tissue (bone, muscle, connective tissue, vasculature, etc.) in any region of the body. Some overgrowth syndromes, characterized by both generalized and lateralized overgrowth, have been associated with an increased risk of tumor development. This may be due to the underlying genetic and epigenetic defects that lead to disrupted cell growth and proliferation pathways resulting in the overgrowth and tumor phenotypes. This chapter focuses on the four most common syndromes characterized by LO: Beckwith-Wiedemann spectrum (BWSp), -related overgrowth spectrum (PROS), Proteus syndrome (PS), and hamartoma tumor syndrome (PHTS). These syndromes demonstrate variable risks for tumor development in patients affected by LO, and we provide a comprehensive literature review of all common tumors reported in patients diagnosed with an LO-related disorder. This review summarizes the current data on tumor risk among these disorders and their associated tumor screening guidelines. Furthermore, this chapter highlights the importance of an accurate diagnosis when a patient presents with LO as similar phenotypes are associated with different tumor risks, thereby altering preventative screening protocols.
PubMed: 33392121
DOI: 10.3389/fped.2020.613260 -
Journal of Hand and Microsurgery Oct 2020This article describes a rare case of giant cell tumor of the tendon sheath (GCTTS) that was developed over the substance of chimeric-free latissimus dorsi and -serratus...
This article describes a rare case of giant cell tumor of the tendon sheath (GCTTS) that was developed over the substance of chimeric-free latissimus dorsi and -serratus -anterior muscle flaps performed for lower limb reconstruction. To our knowledge, development of GCTTS over a free flap is first described in the literature. A 71-year-old -woman was presented with a large protuberant ulcerated tumor mass that was developed over the substance of chimeric free muscle flaps at the foot and ankle. We performed an extensive tumor resection, and the pathology report confirmed the presence of a primary giant cell tumor. The patient was advised to have a below-knee amputation. However, the patient refused the amputation, and 4 months later, she was presented with a metastatic mass proximally at the upper thigh. We believe that the GCTTS was associated with the chronic inflammation of the soft tissue and bones along with the recurrent episodes of infection, mainly due to proteus mirabilis and proteus syndrome (PS). PS may lead to the development of malformations and overgrowth of different tissues in unusual locations. In cases resistant to antibiotics, the radical surgical debridement should be considered as the most effective treatment.
PubMed: 33335372
DOI: 10.1055/s-0039-1679102 -
BMC Urology Dec 2020Transurethral resection of the prostate (TUR-P) is one of the most frequent routine procedures in urology. Because of the semisterile environment, postoperative...
BACKGROUND
Transurethral resection of the prostate (TUR-P) is one of the most frequent routine procedures in urology. Because of the semisterile environment, postoperative infections, including sepsis, are a common complication, with Escherichia coli, Klebsiella spp., Proteus mirabilis or Enterococcus faecalis as frequently isolated pathogens. Facklamia hominis is a gram-positive, facultatively anaerobic, alpha-hemolytic, catalase-negative coccus that was first described in 1997. To date, only a few cases of infectious complications have been described. We report the first case of postoperative bacteremia due to Facklamia hominis after TUR-P.
CASE PRESENTATION
An 82-year-old man developed fever only a few hours after elective TUR-P because of benign prostate syndrome. After cultivation of blood cultures, antibiotic therapy with ceftriaxone was intravenously administered and changed to oral cotrimoxazole before discharge of the afebrile patient. One anaerobic blood culture revealed Facklamia hominis. Under antibiotic therapy, the patient remained afebrile and showed no signs of infections during follow-up.
CONCLUSIONS
Fever and bacteremia are frequent complications after TUR-P. This study is the first report of Facklamia hominis in a postoperative blood culture after TUR-P. To date, there are only a few reports of patients with infectious complications and isolation of Facklamia hominis in various patient samples. Because Facklamia hominis resembles viridans streptococci on blood agar analysis, this pathogen may often be misidentified. In this case identification of Facklamia hominis was possible with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. It has been postulated that Facklamia hominis might be a facultative pathogen and that its incidence will increase in the future.
Topics: Aerococcaceae; Aged, 80 and over; Bacteremia; Gram-Positive Bacterial Infections; Humans; Male; Postoperative Complications; Transurethral Resection of Prostate
PubMed: 33287796
DOI: 10.1186/s12894-020-00762-8 -
Frontiers in Pediatrics 2020Abnormally excessive growth results from perturbation of a complex interplay of genetic, epigenetic, and hormonal factors that orchestrate human growth. Overgrowth... (Review)
Review
Abnormally excessive growth results from perturbation of a complex interplay of genetic, epigenetic, and hormonal factors that orchestrate human growth. Overgrowth syndromes generally present with inherent health concerns and, in some instances, an increased risk of tumor predisposition that necessitate prompt diagnosis and appropriate referral. In this review, we introduce some of the more common overgrowth syndromes, along with their molecular mechanisms, diagnostics, and medical complications for improved recognition and management of patients affected with these disorders.
PubMed: 33194904
DOI: 10.3389/fped.2020.574857