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Cold Spring Harbor Molecular Case... Feb 2020A 20-yr-old man with Proteus syndrome (PS) and somatic mosaicism of the c.49G > A p.(E17K) variant had asymmetric overgrowth of the right frontal and facial bones,...
A 20-yr-old man with Proteus syndrome (PS) and somatic mosaicism of the c.49G > A p.(E17K) variant had asymmetric overgrowth of the right frontal and facial bones, asymmetric spinal overgrowth with thoracolumbar scoliosis, dilatation of the inferior vena cava, testicular cystadenoma, bilateral knee deformities, macrodactyly, and apparent intellectual disability. Miransertib (ARQ 092) is an oral, allosteric, selective pan-AKT inhibitor initially developed for cancer therapeutics, now being evaluated for the treatment of PS. After baseline evaluation, the patient started unblinded treatment of 10 mg oral miransertib daily (∼5 mg/m/day), escalated to 30 mg daily (∼15 mg/m/day), and then to 50 mg daily (∼25 mg/m/day) after 3 mo of treatment. Adverse events included dry mouth, one episode of gingivostomatitis, and loose, painful dentition due to preexisting periodontal disease, all of which resolved spontaneously. After 11 mo of treatment, the patient reported improved general well-being, increased mobility of the ankle, spine, and hands, a subjective decrease in size of the right facial bone overgrowth, and reduced areas of cerebriform connective tissue nevi on the soles. Whole-body MRI findings were stable without apparent disease progression. We conclude that 1 yr of treatment with miransertib was beneficial in this case.
Topics: Alleles; Aminopyridines; Duration of Therapy; Humans; Image Processing, Computer-Assisted; Imidazoles; Magnetic Resonance Imaging; Male; Mutation; Phenotype; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Proteus Syndrome; Proto-Oncogene Proteins c-akt; Young Adult
PubMed: 32014856
DOI: 10.1101/mcs.a004549 -
BMC Medical Genetics Jan 2020Proteus syndrome (PS) is an extremely rare disease characterized by excessive chimeric growth of cells, and progressive and irregular asymmetrical hyperplasia.
BACKGROUND
Proteus syndrome (PS) is an extremely rare disease characterized by excessive chimeric growth of cells, and progressive and irregular asymmetrical hyperplasia.
CASE PRESENTATION
Herein, a PS case with atypical clinical features and syndromes was reported, to improve the understanding of the diagnosis and treatment of the disease. The case was a 3-year-and-11-month-old male child. He was admitted due to a primary diagnosis of McCune-Albright syndrome. After admission, the lesion samples from the milk coffee spots, and nodular thickening skin at hands and feet were subjected to genetic screening. Genetic testing results confirmed the diagnosis of PS.
CONCLUSIONS
Based on the clinical manifestations, laboratory tests, imaging data, and literature reviewing, the etiology, diagnosis, treatment and prognosis of PS have been analyzed and discussed.
Topics: Cell Proliferation; Child; Child, Preschool; Chimera; Diagnosis, Differential; Fibrous Dysplasia, Polyostotic; Humans; Infant; Male; Proteus Syndrome; Rare Diseases
PubMed: 31964351
DOI: 10.1186/s12881-020-0949-x -
F1000Research 2019Overgrowth syndromes are a heterogeneous group of conditions characterized by excessive body growth - localized or generalized - commonly associated with various...
Overgrowth syndromes are a heterogeneous group of conditions characterized by excessive body growth - localized or generalized - commonly associated with various malformities and an increased oncological risk. Here we present the case of a 59-years old man, employed in an office, who suffers from an asymmetric overgrowth of the lower limbs. Currently the patient presents malformations of the lower left limb (hip, knee and ankle), evident on the articular and periarticular level, where there are diffuse exostoses. This case discusses the main occupational concerns relating to the patient's workspace at a high floor level that could create critical issues in the event of an emergency exodus. Given the impossibility of placing the patient in heavy manual activities, employment is limited to office activities. Adjustments were carried out at the patient's workstation, and thus the patient has been recognized as fit to work. Increased frequency of breaks were prescribed in order to allow the physiological alternation of postures. In cases of overgrowth syndromes, the exact identification of the limitations presented by the patient and observations about ambulatory functions must be carefully evaluated in order to modulate the work environment.
PubMed: 34471519
DOI: 10.12688/f1000research.21348.2 -
Anesthesiology Apr 2020
Topics: Airway Management; Child, Preschool; Disease Management; Humans; Male; Proteus Syndrome; Supraglottitis
PubMed: 31743138
DOI: 10.1097/ALN.0000000000003058 -
Mikrobiyoloji Bulteni Oct 2019Purple urine bag syndrome (PUBS) is a rare syndrome characterized by production of indigo (blue) and indirubin (red) pigments due to bacterial colonization in urinary... (Review)
Review
Purple urine bag syndrome (PUBS) is a rare syndrome characterized by production of indigo (blue) and indirubin (red) pigments due to bacterial colonization in urinary catheter. The pathogenesis of PUBS is related to the combination of these two pigments produced from the metabolism of tryptophan. Tryptophan turns into indole by deamination, indole turns into indoxyl sulphate by hepatic conjugation and indoxyl sulphate is secreted into urine. Sulphatases and phosphatases enzymes produced by bacteria like Providencia stuartii and Providencia rettgeri, Klebsiella pneumoniae, Proteus mirabilis, Escherichia coli, Enterococcus spp., Morganella morganii, Pseudomonas aeruginosa, Citrobacter spp. and group B streptococci convert indoxyl sulphate to indoxyl. In the urinary tract, oxidation of indoxyl results in the production of indigo and indirubin pigments. These pigments react with polyvinyl chloride (PVC) lining of the urinary catheter bag and the reaction results purple discoloration of urine. Urine discoloration is very important clinical sign in the differential diagnosis of several pathological conditions such as hematuria, urinary system tumors and drug side effects and may be disquieting for patients, families and healthcare workers. Purple urine discoloration is rarely reported in the literature and it is generally associated with urinary tract infection. In this report, a 60 years old woman with a past medical history of significant chronic kidney disease undergoing regular hemodialysis, chronic constipation and hepatitis B was admitted to our neurology clinic because of acute intracerebral hemorrhage. She had confusion and right hemiplegia in her neurological examination and required urinary catheterization due to immobilization. Red coloration was observed in urine on the tenth hospital day. Although this coloration was thought to be hematuria, according to urine examination it was not hematuria. Then urine color turned into purple within two days. The next day, because of fever, full blood count and other blood investigations were performed and urine was sent to the laboratory for culture. Empirical piperacillin-tazobactam and teicoplanin antibiotic treatments were commenced. In the urine culture, 105 cfu/ml Enterococcus faecalis was isolated. According to the antibiotic susceptibility results the therapy was changed and meropenem was added to the treatment. For her constipation, supportive managements such as hydration, nutrition and laxative treatment were applied. After all the treatments, the patient's constipation regressed, the urine had become normal colored and the following urine cultures were not revealed any bacterial growth. As in this case, when the urine discoloration occurs, PUBS should be kept in mind which is especially seen in elderly female patients with chronic constipation, urinary catheterization, urinary tract infection and renal failure.
Topics: Anti-Bacterial Agents; Female; Humans; Middle Aged; Treatment Outcome; Urinary Catheters; Urinary Tract Infections; Urine
PubMed: 31709943
DOI: 10.5578/mb.68616 -
American Journal of Medical Genetics.... Dec 2019Phenotype-based diagnostic criteria were developed for Proteus syndrome in 1999 and updated in 2006. Subsequently, the causative mosaic gene alteration was discovered,...
Phenotype-based diagnostic criteria were developed for Proteus syndrome in 1999 and updated in 2006. Subsequently, the causative mosaic gene alteration was discovered, the c.49G>A p.E17K variant in AKT1. As well, a number of overlapping overgrowth disorders attributable to mosaic PIK3CA variants have now been characterized, leading to the designation of PIK3CA-related overgrowth spectrum (PROS). Finally, ongoing work to better characterize Proteus syndrome has led to identification of additional features of that disorder that could be useful in diagnostic criteria. We have taken the opportunity of these discoveries to re-evaluate the Proteus syndrome diagnostic criteria. Here we propose a new set of diagnostic criteria that establishes a weighted, point-based system for the phenotypic attributes and then integrates that with the potential molecular test results to result in one of two designations: AKT1-related Proteus syndrome or AKT1-related overgrowth spectrum. A patient whose only manifestation is an AKT1 c.49G>A-positive tumor would receive neither of these designations. Here we review the rational basis of diagnostic criteria and argue that a unitary diagnostic entity is a distinct gene-phenotype dyad and that this should be the model for all mendelian disorders. The gene-alone or phenotype-alone approach is inadequate to rigorously delineate a unitary diagnostic entity.
Topics: Genotype; Humans; Phenotype; Proteus Syndrome; Proto-Oncogene Proteins c-akt
PubMed: 31692258
DOI: 10.1002/ajmg.c.31744 -
Cold Spring Harbor Perspectives in... May 2020Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden... (Review)
Review
Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline mutation. Furthermore, outside of the familial setting, somatic variants of occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a mutation. Detection of a germline mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.
Topics: Autism Spectrum Disorder; Biomarkers, Tumor; Genes, Tumor Suppressor; Genetic Testing; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Molecular Targeted Therapy; Neoplasms; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases
PubMed: 31615872
DOI: 10.1101/cshperspect.a037127 -
Einstein (Sao Paulo, Brazil) 2020A 65-year-old male with a history of urinary tract trauma requiring cystotomy and chronic bladder catheterization, presenting with chronic and uninvestigated changes in...
A 65-year-old male with a history of urinary tract trauma requiring cystotomy and chronic bladder catheterization, presenting with chronic and uninvestigated changes in the color of the urine bag system, with no urine color change, and positive urine culture for Proteus mirabilis . These characteristics refer to the purple urine bag syndrome, a not weel-known condition, with a benign course in most cases, and associated with urinary tract infection in patients with chronic bladder catheterization. Although it is characterized by marked changes, it is underdiagnosed by healthcare professionals.
Topics: Aged; Catheter-Related Infections; Humans; Male; Proteus mirabilis; Risk Factors; Syndrome; Urinary Reservoirs, Continent; Urinary Tract Infections; Urine
PubMed: 31553357
DOI: 10.31744/einstein_journal/2020RC5063 -
American Journal of Medical Genetics.... Dec 2019Increased risk of thromboembolism has been recognized in individuals with mosaic overgrowth disorders, Proteus syndrome (PS) and PIK3CA-related overgrowth spectrum...
Increased risk of thromboembolism has been recognized in individuals with mosaic overgrowth disorders, Proteus syndrome (PS) and PIK3CA-related overgrowth spectrum (PROS), including Klippel-Trenaunay syndrome and CLOVES syndrome. PS and PROS have distinct, yet overlapping clinical findings and are caused by somatic pathogenic variants in the PI3K/AKT gene signaling pathway. PS is caused by a single somatic activating AKT1 c.49G > A p.E17K variant while PROS can be caused one of multiple variants in PIK3CA. The role of prothrombotic factors, endothelial cell adhesion molecules, and vascular malformations in both PS and PROS have not been previously investigated. A pilot study of prospective clinical and laboratory evaluations with the purposes of identifying potential risk factors for thrombosis was conducted. Doppler ultrasounds and magnetic resonance angiogram/ venography (MRA/MRV) scans identified vascular malformations in PS and PROS that were not appreciated on physical examination. Abnormal D-dimers (0.60-2.0 mcg/ml) occurred in half of individuals, many having vascular malformations, but no thromboses. Soluble vascular endothelial markers, including thrombomodulin, soluble vascular adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM), E-selectin, and P-selectin were significantly higher in PS and PROS compared to controls. However, no single attribute was identified that explained the risk of thrombosis. Predisposition to thrombosis is likely multifactorial with risk factors including chronic stasis within vascular malformations, stasis from impaired mobility (e.g., following surgery), decreased anticoagulant proteins, and effects of AKT1 and PIK3CA variants on vascular endothelium. Based on our findings, we propose clinical recommendations for surveillance of thrombosis in PS and PROS.
Topics: Adolescent; Adult; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases; Female; Genetic Predisposition to Disease; Growth Disorders; Humans; Infant; Male; Middle Aged; Pilot Projects; Prospective Studies; Proteus Syndrome; Thrombosis; Young Adult
PubMed: 31490637
DOI: 10.1002/ajmg.c.31735 -
Cancer Chemotherapy and Pharmacology Oct 2019This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal...
PURPOSE
This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal antibody targeting activin receptor like kinase 1 (ALK-1), in combination with regorafenib in patients with refractory metastatic colorectal cancer.
METHODS
The first stage of this study was a standard "3 + 3" open-label dose-escalation scheme. Cohorts of 3-6 subjects were started with 120 mg of regorafenib given PO daily for 3 weeks of a 4 week cycle, plus 4.5 mg/kg of PF-03446962 given IV every 2 weeks. Doses of both drugs were adjusted according to dose-limiting toxicities (DLT). Plasma was collected for multiplexed ELISA analysis of factors related to tumor growth and angiogenesis.
RESULTS
Seventeen subjects were enrolled, of whom 11 were deemed evaluable. Seven subjects were enrolled at dose level 1, and four were enrolled at level - 1. Overall, three DLTs were observed during the dose-escalation phase: two in level 1 and one in level - 1. A planned dose-expansion cohort was not started due to early termination of the clinical trial. Common adverse events were infusion-related reaction, fatigue, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dehydration, nausea, back pain, anorexia, and diarrhea. One subject achieved stable disease for 5.5 months, but discontinued treatment due to adverse events.
CONCLUSIONS
The regimen of regorafenib and PF-03446962 was associated with unacceptable toxicity and did not demonstrate notable clinical activity in patients with refractory metastatic colorectal cancer.
Topics: Activin Receptors, Type II; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Early Termination of Clinical Trials; Enzyme Inhibitors; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Phenylurea Compounds; Pyridines
PubMed: 31444620
DOI: 10.1007/s00280-019-03916-0