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American Journal of Medical Genetics.... Sep 2017Patients with overgrowth and complex vascular malformation syndromes, including Proteus syndrome have an increased risk of thromboembolism. Proteus syndrome is a mosaic,...
Patients with overgrowth and complex vascular malformation syndromes, including Proteus syndrome have an increased risk of thromboembolism. Proteus syndrome is a mosaic, progressive overgrowth disorder involving vasculature, skin, and skeleton, and caused by a somatic activating mutation in AKT1. We conducted a comprehensive review of the medical histories and hematologic evaluations of 57 patients with Proteus syndrome to identify potential risk factors for thrombosis. We found that six of ten patients, who were deceased, died secondary to deep venous thrombosis and/or pulmonary embolism. Of the remaining 47 living patients, six had thromboembolic events that all occurred postoperatively and in an affected limb. Eleven of 21 patients had an abnormal hypercoagulable panel including Factor V Leiden heterozygotes, antithrombin III deficiency, positive lupus anticoagulant, or Protein C or S deficiencies. We observed that eight of 17 patients had an abnormal D-dimer level >0.5 mcg/dl, but deep venous thromboses occurred in only four of those with D-dimer >1.0 mcg/dl. We conclude that the predisposition to thrombosis is likely to be multifaceted with risk factors including vascular malformations, immobility, surgery, additional prothrombotic factors, and possible pathophysiologic effects of the somatic AKT1 mutation on platelet function or the vascular endothelium. The D-dimer test is useful as a screen for thromboembolism, although the screening threshold may need to be adjusted for patients with this disorder. We propose developing a registry to collect D-dimer and outcome data to facilitate adjustment of the D-dimer threshold for Proteus syndrome and related disorders, including PIK3CA-Related Overgrowth Spectrum.
Topics: Adolescent; Adult; Aged; Antithrombin III Deficiency; Child; Child, Preschool; Endothelium, Vascular; Factor V; Female; Fibrin Fibrinogen Degradation Products; Humans; Lupus Coagulation Inhibitor; Male; Middle Aged; Protein C Deficiency; Protein S Deficiency; Proteus Syndrome; Proto-Oncogene Proteins c-akt; Pulmonary Embolism; Risk Factors; Thrombosis
PubMed: 28627093
DOI: 10.1002/ajmg.a.38311 -
Postmortem Diagnosis of the Proteus Syndrome by Next Generation Sequencing of Affected Brain Tissue.Academic Forensic Pathology Jun 2022We report a case of a somatic overgrowth syndrome diagnosed at forensic autopsy with the aid of next generation sequencing as Proteus syndrome. Somatic overgrowth...
We report a case of a somatic overgrowth syndrome diagnosed at forensic autopsy with the aid of next generation sequencing as Proteus syndrome. Somatic overgrowth syndromes result from spontaneous somatic mutations that arise early in development and display a mosaic pattern of expression in patient tissues. Due to the temporal and anatomic heterogeneity of these syndromes, phenotypes vary widely, resulting in clinical overlap. Furthermore, the variable ratio of mutated to nonmutated cells in patient tissue can result in low-level mutations that could be missed using Sanger sequencing. Due to these factors, recent literature points to next generation sequencing (NGS) as an adjunct to diagnosis of these rare entities. A male in his fourth decade of life presented to our forensic autopsy service with physical features suggestive of a somatic overgrowth syndrome. Due to the paucity of clinical information accompanying the individual, a definitive diagnosis based on physical characteristics, alone, was not possible. Next generation sequencing of affected formalin-fixed and paraffin-embedded brain tissue confirmed the presence of the variant in (c.49G>A, p.Glu17Lys, in 14.13% of reads) found in Proteus syndrome. To our knowledge, this is the first report of the mosaic variant of detected in brain tissue and the first reported case of a postmortem diagnosis of Proteus syndrome with the aid of NGS. We conclude that NGS can be used as an adjunctive method to support a specific diagnosis among the somatic overgrowth syndromes postmortem in the absence of sufficient clinical history.
PubMed: 35799996
DOI: 10.1177/19253621221097294 -
Iranian Journal of Otorhinolaryngology Nov 2023Proteus syndrome (PS) is a rare genetic disorder usually caused by mutations in AKT1 or PTEN genes, characterized by multiple, asymmetric tissue overgrowth with high...
INTRODUCTION
Proteus syndrome (PS) is a rare genetic disorder usually caused by mutations in AKT1 or PTEN genes, characterized by multiple, asymmetric tissue overgrowth with high clinical variability. Sinonasal neuroendocrine carcinomas (SNEC) are exceptionally rare tumors encountered in the ethmoid sinus, nasal cavity, or maxillary sinus.
CASE REPORT
We report a 35-year-old patient with PS, who underwent successful surgical removal of a well-differentiated SNEC obstructing his nasal cavity and highlight the role of the otolaryngologist for safe airway management, minimal surgical intervention and coordination of the multidisciplinary care. Histologically, focally hyperplastic mucosal epithelium of respiratory type of the nasal chamber was noticed along with seromucinous glands and capillary congestion of the subepithelial fibrovascular tissue. The limited presence of neoplastic tissue with histomorphological and immunophenotypic features of a neuroendocrine neoplasm was focally observed. Tumor cells grow in the form of islets within a vascular stroma; these neoplastic cells are immunohistochemically positive for synaptophysin, CD56, EMA, Ki67 (low expression, cell proliferation rate: 2%), CD31, chromogranin and pancytokeratin AE1 / AE3 as well as for S-100 protein (weak intensity).
CONCLUSIONS
This first description of a SNEC in a PS patient, might hint towards a common basis between the two conditions, due to the mosaic AKT1 variant and an activated AKT/PIK3CA/PTEN pathway.
PubMed: 38074478
DOI: 10.22038/IJORL.2023.73128.3472 -
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 -
European Journal of Case Reports in... 2016We present the case of an elderly woman with long-term indwelling urinary catheter use whose urine turned purple due to a urinary tract infection.
UNLABELLED
We present the case of an elderly woman with long-term indwelling urinary catheter use whose urine turned purple due to a urinary tract infection.
LEARNING POINTS
Purple urine bag syndrome is secondary to urinary tract infections with indigo- and indirubin-producing bacteria and affects typically institutionalized and chronically catheterized patients., and are the main culprit.It may reflect only asymptomatic bacteriuria and therefore the need for antibiotic treatment must be carefully addressed and individualized.Catheter sanitation, constipation avoidance and prompt removal of unnecessary catheters are key to prevention.
PubMed: 30755901
DOI: 10.12890/2016_000507 -
Anais Brasileiros de Dermatologia 2023
Topics: Humans; Proteus Syndrome; Limb Deformities, Congenital; Fingers; Hypertrophy; Skin Diseases; Vascular Malformations
PubMed: 36754650
DOI: 10.1016/j.abd.2021.11.012 -
Radiology Case Reports 2014The extremely rare Proteus Syndrome is a hamartomatous congenital syndrome with substantial variability between clinical patient presentations. The diagnostic criteria...
The extremely rare Proteus Syndrome is a hamartomatous congenital syndrome with substantial variability between clinical patient presentations. The diagnostic criteria consist of a multitude of clinical findings including hemihypertrophy, macrodactyly, epidermal nevi, subcutaneous hamartomatous tumors, and bony abnormalities. These clinical findings correlate with striking radiographic findings.
PubMed: 27186241
DOI: 10.2484/rcr.v9i2.911 -
Genetics in Medicine : Official Journal... Dec 2017PurposeProteus syndrome is a rare mosaic overgrowth disorder that is associated with severe complications. While anecdotal data have suggested that the life span of...
PurposeProteus syndrome is a rare mosaic overgrowth disorder that is associated with severe complications. While anecdotal data have suggested that the life span of affected patients is reduced, this has not been measured. Mortality data on rare diseases is critical for assessing treatments and other interventions.MethodsTo address this we used the clinical research records of 64 patients in a longitudinal natural history cohort at the National Institutes of Health to ascertain the data in an organized manner and estimate survival using a Kaplan-Meier approach.ResultsThe median age of diagnosis was 19 months. Based on this analysis, there was 25% probability of death by 22 years of age. Ten of the 11 patients who died were younger than 22 years of age, and there was only a single death after this age.ConclusionThese data quantify the risk of premature death in Proteus syndrome, which can be used to support interventions and trials. Although the risk of death is substantial, the fact that only one patient died after 22 years of age supports anecdotal evidence that the disease process moderates after the end of adolescence. Interventions to reduce mortality should be targeted to the pediatric age range.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Kaplan-Meier Estimate; Male; Proteus Syndrome; Young Adult
PubMed: 28661492
DOI: 10.1038/gim.2017.65 -
Tidsskrift For Den Norske Laegeforening... Mar 2019Purple urine bag syndrome (PUBS) can occur in cases of bacteriuria with species expressing enzymes capable of converting tryptophan metabolites to red and blue pigments...
BACKGROUND
Purple urine bag syndrome (PUBS) can occur in cases of bacteriuria with species expressing enzymes capable of converting tryptophan metabolites to red and blue pigments which are excreted in urine, leaving a characteristic purple colour. Risk factors include urinary catheterisation, constipation and chronic kidney disease. Treatment includes catheter replacement, and antibiotics in case of urinary tract infection.
CASE PRESENTATION
A man in his 70s with myelodysplastic syndrome, stage 5 chronic kidney disease and chronic indwelling urinary catheterisation due to benign prostatic hyperplasia was admitted for transfusion for symptomatic anaemia. On the second day of hospitalisation, his urine turned purple. There was no sign of transfusion reaction, haemoglobinuria, myoglobinuria or bilirubinuria. Urine cultures were positive for Proteus vulgaris and Enterococcus faecalis, two species associated with PUBS.
INTERPRETATION
The constellation was consistent with PUBS. His bacteriuria was considered colonisation not requiring antibiotic treatment. The catheter was replaced and the urine colour returned to normal.
Topics: Aged; Bacteriuria; Catheter-Related Infections; Enterococcus faecalis; Humans; Male; Proteus vulgaris; Urinary Catheters; Urinary Tract Infections; Urine
PubMed: 30917642
DOI: 10.4045/tidsskr.18.0677 -
Biomedicine & Pharmacotherapy =... Sep 2023The pleckstrin homology [PH] domain is a structural fold found in more than 250 proteins making it the 11th most common domain in the human proteome. 25% of family... (Review)
Review
The pleckstrin homology [PH] domain is a structural fold found in more than 250 proteins making it the 11th most common domain in the human proteome. 25% of family members have more than one PH domain and some PH domains are split by one, or several other, protein domains although still folding to give functioning PH domains. We review mechanisms of PH domain activity, the role PH domain mutation plays in human disease including cancer, hyperproliferation, neurodegeneration, inflammation, and infection, and discuss pharmacotherapeutic approaches to regulate PH domain activity for the treatment of human disease. Almost half PH domain family members bind phosphatidylinositols [PIs] that attach the host protein to cell membranes where they interact with other membrane proteins to give signaling complexes or cytoskeleton scaffold platforms. A PH domain in its native state may fold over other protein domains thereby preventing substrate access to a catalytic site or binding with other proteins. The resulting autoinhibition can be released by PI binding to the PH domain, or by protein phosphorylation thus providing fine tuning of the cellular control of PH domain protein activity. For many years the PH domain was thought to be undruggable until high-resolution structures of human PH domains allowed structure-based design of novel inhibitors that selectively bind the PH domain. Allosteric inhibitors of the Akt1 PH domain have already been tested in cancer patients and for proteus syndrome, with several other PH domain inhibitors in preclinical development for treatment of other human diseases.
Topics: Humans; Pleckstrin Homology Domains; Binding Sites; Blood Proteins; Phosphoproteins; Protein Binding
PubMed: 37399719
DOI: 10.1016/j.biopha.2023.115024