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Cureus May 2024An uncommon congenital hamartomatous disorder called Proteus syndrome is characterized by multifocal tissue expansion originating from all three germinal layers....
An uncommon congenital hamartomatous disorder called Proteus syndrome is characterized by multifocal tissue expansion originating from all three germinal layers. Diagnosis mainly relies on clinical and radiological criteria. Here, we present a case of a 13-year-old female child exhibiting bony, soft tissue, and vascular abnormalities, along with developmental delay. We conclude by highlighting the importance of imaging studies in conjunction with physical examination, which are characterized by general and specific criteria to diagnose this rare condition until a specific gene test becomes available.
PubMed: 38860105
DOI: 10.7759/cureus.60072 -
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 -
International Journal of Dermatology May 2024
PubMed: 38757487
DOI: 10.1111/ijd.17119 -
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 -
Clinical Case Reports Oct 2023Proteus syndrome is a rare genetic disease characterized by an asymmetrical growth of individual parts of the body and has only been described in single cases. This...
Proteus syndrome is a rare genetic disease characterized by an asymmetrical growth of individual parts of the body and has only been described in single cases. This patient presented with recurrent manifestations of a laryngeal and hypopharyngeal lymphangioma, which were treated with laser surgery, systemic therapy, and sclerotherapy. The reported data depict the diagnosis and treatment in the department of otorhinolaryngology, head and neck surgery of the university hospital Heidelberg from 2019 until May 2023. The recurrent endoscopy of the upper airway was performed using a flexible HD-endoscope and the Visera Elite video tower from Olympus, Hamburg. The 29-year old female patient initially presented in February 2019 with stridor and exertional dyspnea due to a lymphatic malformation of the left larynx and hypopharynx. In April 2019 there was no improvement by sclerotherapy with Picibanil, so that systemic therapy with the PIK3CA inhibitor alpelisib was initiated (03-07/2020) and discontinued due to a high side effect profile. In the course of 2021-2023, three microlaryngoscopies with laser surgical resection and renewed sclerotherapy of the lymphangioma with Picibanil were carried out due to fluctuating findings. After these interventions a stable disease could be established until May 2023. Laser surgical therapy is currently described as the therapy of choice in lymphangiomas in the head and neck region and also showed the highest effectiveness in our patient. In case of airway obstruction in particular, it can bring rapid symptom relief. Alternatively, and with a lower surgical risk, local improvements have been reported by sclerotherapy, which was less effective in the presented case. Rare syndromic diseases require multidisciplinary collaboration. In the case of laryngeal lymphangiomatosis, other treatment options should be considered in addition to surgical excision, especially in the case of recurrence.
PubMed: 37854262
DOI: 10.1002/ccr3.8073 -
Life (Basel, Switzerland) Jul 2023AKT1 is a serine/threonine kinase necessary for the mediation of apoptosis, angiogenesis, metabolism, and cell proliferation in both normal and cancerous cells. The...
BACKGROUND
AKT1 is a serine/threonine kinase necessary for the mediation of apoptosis, angiogenesis, metabolism, and cell proliferation in both normal and cancerous cells. The mutations in the AKT1 gene have been associated with different types of cancer. Further, the AKT1 gene mutations are also reported to be associated with other diseases such as Proteus syndrome and Cowden syndromes. Hence, this study aims to identify the deleterious AKT1 missense SNPs and predict their effect on the function and structure of the AKT1 protein using various computational tools.
METHODS
Extensive in silico approaches were applied to identify deleterious SNPs of the human AKT1 gene and assessment of their impact on the function and structure of the AKT1 protein. The association of these highly deleterious missense SNPs with different forms of cancers was also analyzed. The in silico approach can help in reducing the cost and time required to identify SNPs associated with diseases.
RESULTS
In this study, 12 highly deleterious SNPs were identified which could affect the structure and function of the AKT1 protein. Out of the 12, four SNPs-namely, G157R, G159V, G336D, and H265Y-were predicted to be located at highly conserved residues. G157R could affect the ligand binding to the AKT1 protein. Another highly deleterious SNP, R273Q, was predicted to be associated with liver cancer.
CONCLUSIONS
This study can be useful for pharmacogenomics, molecular diagnosis of diseases, and developing inhibitors of the AKT1 oncogene.
PubMed: 37511907
DOI: 10.3390/life13071532 -
Indian Dermatology Online Journal 2024International Society for the Study of Vascular Anomalies classification defines Congenital Limb Overgrowth Vascular Syndromes (CLOS) as a subset of vascular syndromes...
International Society for the Study of Vascular Anomalies classification defines Congenital Limb Overgrowth Vascular Syndromes (CLOS) as a subset of vascular syndromes with other abnormalities that present with unilateral limb overgrowth. It includes Klippel-Trenaunay Syndrome, Parkes-Weber Syndrome, CLOVES (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis) Syndrome, Proteus Syndrome, PTEN Hamartomatous Syndrome, and Fibroadipose Vascular Anomaly. Due to their rare and complex nature, a multidisciplinary approach to diagnosis and treatment is required. A thorough clinical and radiological workup can go miles in reflecting on the patient's outcome. Here we report five cases of CLOS with their detailed dermato-radiological profiles.
PubMed: 38845672
DOI: 10.4103/idoj.idoj_500_23 -
Joint Diseases and Related Surgery Aug 2023Compartment syndrome is a well-described clinical condition and is considered an orthopedic emergency affecting individuals of all ages. A typical scenario for acute...
Compartment syndrome is a well-described clinical condition and is considered an orthopedic emergency affecting individuals of all ages. A typical scenario for acute compartment syndrome involves lower limb fractures or crush injuries. However, physicians may occasionally encounter atypical presentations, defined as atypical compartment syndrome (ACS). A 38-year-old, left-handed male patient without any comorbidities developed ACS of the forearm and clinical presentation of sepsis after a small penetrating injury to his right forearm. He developed ACS secondary to infected hematoma and subsequent soft tissue infection caused by Proteus mirabilis and Morganella morganii. Both bacteria infected the patient by direct contamination after injury with a knife, resulting in multifloral contamination. The patient was successfully treated with reconstructive surgery. In conclusion, ACS secondary to this type of penetrating injury shows a subtle clinical course at the time of hospital admission and can insidiously progress from an infected hematoma, posing a serious threat to the limb or even cause mortality. Good extremity function without any disability can be achieved with an accurate diagnosis during the initial evaluation of the patient in the emergency department and prompt surgical intervention followed by appropriate reconstructive methods.
Topics: Adult; Humans; Male; Coinfection; Compartment Syndromes; Forearm; Hematoma; Morganella morganii; Proteus mirabilis
PubMed: 37750284
DOI: 10.52312/jdrs.2023.1066 -
BioRxiv : the Preprint Server For... Jan 2024Vascular malformation, a key clinical phenotype of Proteus syndrome, lacks effective models for pathophysiological study and drug development due to limited patient...
Vascular malformation, a key clinical phenotype of Proteus syndrome, lacks effective models for pathophysiological study and drug development due to limited patient sample access. To bridge this gap, we built a human vascular organoid model replicating Proteus syndrome's vasculature. Using CRISPR/Cas9 genome editing and gene overexpression, we created induced pluripotent stem cells (iPSCs) embodying the Proteus syndrome-specific AKT point mutation for organoid generation. Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections. This could be due to the significant vasculogenesis induced by AKT overactivation. This phenomenon likely stems from boosted vasculogenesis triggered by AKT overactivation, leading to increased vascular sprouting. Additionally, a notable increase in dysfunctional PDGFR+ mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids. The application of AKT inhibitors (ARQ092, AZD5363, or GDC0068) reversed the vascular malformations; the inhibitors' effectiveness was directly linked to reduced connectivity in the organoids. In summary, our study introduces an innovative in vitro model combining organoid technology and gene editing to explore vascular pathophysiology in Proteus syndrome. This model not only simulates Proteus syndrome vasculature but also holds potential for mimicking vasculatures of other genetically driven diseases. It represents an advance in drug development for rare diseases, historically plagued by slow progress.
PubMed: 38328122
DOI: 10.1101/2024.01.26.577324 -
Healthcare (Basel, Switzerland) Aug 2023Purple urine bag syndrome (PUBS) is an uncommon, but usually benign, underrecognized clinical condition with the distressing presentation of purple, blue or reddish...
Purple urine bag syndrome (PUBS) is an uncommon, but usually benign, underrecognized clinical condition with the distressing presentation of purple, blue or reddish discoloration of a patient's catheter bag and tubing in the setting of catheter-associated urinary tract infections (UTIs). PUBS is the result of the complex metabolic pathway of the dietary essential amino acid tryptophan. Its urinary metabolite, indoxyl sulfate, is converted into red and blue byproducts (indirubin and indigo) in the presence of the bacterial enzymes indoxyl sulfatase and phosphatase. The typical predisposing factors are numerous and include the following: female gender, advanced age, long-term catheterization and immobilization, constipation, institutionalization, dementia, increased dietary intake of tryptophan, chronic kidney disease, alkaline urine, and spinal cord injury (SCI). Here, we present a case of PUBS in a home-dwelling elderly female patient with a history of long-term immobility after a pathological spinal fracture, long-term catheterization, constipation, and malignant disease in remission. Urine culture was positive for . This state can be alarming to both patients and physicians, even if the patient is asymptomatic. Healthcare professionals and caregivers need to be aware of this unusual syndrome as an indicator of bacteriuria in order to initiate proper diagnostics and treatment.
PubMed: 37628449
DOI: 10.3390/healthcare11162251