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Orphanet Journal of Rare Diseases Feb 2024Proteus syndrome is an ultra-rare mosaic overgrowth disorder. Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to...
BACKGROUND
Proteus syndrome is an ultra-rare mosaic overgrowth disorder. Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention. This retrospective study seeks to quantify the radiographic features of Proteus syndrome-associated lung disease using computed tomography (CT) of the chest. The first method derives a Cystic Lung Score (CLS) by using a computer-aided diagnostic tool to quantify the fraction of cystic involvement of the lung. The second method yields a Clinician Visual Score (CVS), an observer reported scale of severity based on multiple radiographic features. The aim of this study was to determine if these measurements are associated with clinical symptoms, pulmonary function test (PFT) measurements, and if they may be used to assess progression of pulmonary disease.
RESULTS
One hundred and thirteen imaging studies from 44 individuals with Proteus syndrome were included. Dyspnea and oxygen use were each associated with higher CLS (p = 0.001 and < 0.001, respectively) and higher CVS (p < 0.001 and < 0.001). Decreases in percent predicted FVC, FEV, and DLCO each correlated with increased CLS and CVS. The annual increase of CLS in children, 5.6, was significantly greater than in adults, 1.6. (p = 0.03). The annual increase in CVS in children, 0.4, was similar to adults, 0.2 (p = 0.36).
CONCLUSIONS
Proteus syndrome-associated lung disease is progressive. The rate of cystic progression is increased in children. Increased scores in CLS and CVS were associated with clinical symptoms and decreased pulmonary function. Both methods were able to detect change over time and were associated with clinically meaningful outcomes which may enable their use in interventional studies.
Topics: Adult; Child; Humans; Proteus Syndrome; Retrospective Studies; Lung; Tomography, X-Ray Computed; Lung Diseases
PubMed: 38321508
DOI: 10.1186/s13023-023-03013-9 -
Annual Review of Genomics and Human... 2015Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately... (Review)
Review
Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately 1/5,000 births, and some are lethal. Since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders, genetic causes of 56 skeletal disorders have been uncovered. This remarkable rate of discovery is largely due to the expanded use of high-throughput genomic technologies. In this review, we discuss these recent discoveries and our understanding of the molecular mechanisms behind these skeletal dysplasia phenotypes. We also cover potential therapies, unusual genetic mechanisms, and novel skeletal syndromes both with and without known genetic causes. The acceleration of skeletal dysplasia genetics is truly spectacular, and these advances hold great promise for diagnostics, risk prediction, and therapeutic design.
Topics: Animals; Body Height; Bone Diseases, Developmental; Disease Models, Animal; Dwarfism; Epigenesis, Genetic; High-Throughput Nucleotide Sequencing; Histone Acetyltransferases; Humans; Mice; MicroRNAs; Mutation; Osteochondrodysplasias; Proteus Syndrome
PubMed: 25939055
DOI: 10.1146/annurev-genom-090314-045904 -
Postepy Dermatologii I Alergologii Aug 2023Lipomas are usually sporadic, asymptomatic lesions, and their clinical and histologic presentation does not pose diagnostic difficulties. In ambiguous cases, however,... (Review)
Review
Lipomas are usually sporadic, asymptomatic lesions, and their clinical and histologic presentation does not pose diagnostic difficulties. In ambiguous cases, however, knowledge of genetics is necessary. HMGA2 expression in adipose cells enables the differentiation of normal adipose tissue from lipoma and liposarcoma. Moreover, lipomas can be associated with genetic diseases, such as multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson's disease, or mitochondrial diseases. Lipomas can run in families (familial multiple lipomatosis) or be a part of genetic syndromes such as PTEN hamartoma tumor syndrome, Proteus syndrome, and Pai syndrome. This study aims to present the genetic basis of lipomas and diseases in which these lesions occur in the clinical picture.
PubMed: 37692275
DOI: 10.5114/ada.2023.129529 -
Case Reports in Orthopedics 2022In the setting of below-knee amputation, compartment syndrome is a rare complication. Early clinical symptoms of an acute compartment syndrome following below-knee...
In the setting of below-knee amputation, compartment syndrome is a rare complication. Early clinical symptoms of an acute compartment syndrome following below-knee amputation can mimic or be masked by postoperative pain management. We present the case of a 38-year-old male with a significant past medical history of Proteus syndrome who underwent an elective transtibial below-knee amputation. Following surgery, the patient had extensive postoperative pain and high pain medication requirements and returned to the operating room for irrigation and debridement due to suspicion of an infection. Upon return to the operating room to manage the infection, the necrotic tissue was discovered and removed which had developed due to a suspected missed acute compartment syndrome. The necrotic tissue secondary to the compartment syndrome subsequently resulted in infection. Multiple irrigation and debridement procedures were performed to further manage the infection, and ultimately, the patient was deemed stable for discharge. Acute compartment syndrome (ACS) following below-knee amputation (BKA) is a rarely documented but critical complication. This case describes the unique setting in which a compartment syndrome can be masked due to postoperative pain management and infection. Orthopedic surgeons should be aware of the varying risk factors and presentations of an acute compartment syndrome (ACS) as it can occur and is a devastating complication.
PubMed: 35237457
DOI: 10.1155/2022/1256823 -
Human Molecular Genetics Sep 2019Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G > A p.(E17K) in AKT1. The presentation in affected...
Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G > A p.(E17K) in AKT1. The presentation in affected individuals is variable, with a diversity of tissues demonstrating abnormalities. Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors. We used two methods to create mouse models that had endogenously-regulated mosaic expression of the Proteus syndrome variant. Variant allele fractions (VAFs) ranged from 0% to 50% across numerous tissues in 44 Proteus syndrome mice. Mice were phenotypically heterogeneous with lesions rarely observed before 12 months of age. VMs were the most frequent finding with a total of 69 found in 29 of 44 Proteus syndrome mice. Twenty-eight cysts and ectasia, frequently biliary, were seen in 22 of 44 Proteus syndrome mice. Varying levels of mammary hyperplasia were seen in 10 of 16 female Proteus syndrome mice with other localized regions of hyperplasia and stromal expansion noted in several additional animals. Interestingly, 27 of 31 Proteus syndrome animals had non-zero blood VAF that is in contrast to the human disorder where it is rarely seen in peripheral blood. Identification of variant-positive cells by green fluorescent protein (GFP) staining in chimeric Proteus syndrome mice showed that in some lesions, hyperplastic cells were predominantly GFP/Akt1E17K-positive and showed increased pAKT signal compared to GFP-negative cells. However, hyperplastic mammary epithelium was a mixture of GFP/Akt1E17K-positive and negative cells with some GFP/Akt1E17K-negative cells also having increased pAKT signal suggesting that the variant-positive cells can induce lesion formation in a non-cell autonomous manner.
Topics: Alleles; Animals; Biopsy; Disease Models, Animal; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Genotype; Humans; Mice; Mutation; Phenotype; Proteus Syndrome; Proto-Oncogene Proteins c-akt
PubMed: 31194862
DOI: 10.1093/hmg/ddz116 -
Seminars in Pediatric Surgery Oct 2020Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial... (Review)
Review
Overgrowth syndromes represent a diverse group of disorders with overlapping features. Interdisciplinary management by a team of experts in vascular anomalies is crucial for establishing the correct diagnosis and optimizing outcomes for these patients. Unique management considerations include increased risk for thrombosis and in some cases, cancer. In recent years, research has demonstrated that these disorders are primarily caused by somatic mutations in growth pathways, particularly the PI3K-mTOR pathway. This improved understanding had led to promising new therapies for this group of patients.
Topics: Child; Hamartoma Syndrome, Multiple; Humans; Klippel-Trenaunay-Weber Syndrome; Lipoma; Musculoskeletal Abnormalities; Nevus; Proteus Syndrome; Sturge-Weber Syndrome; Vascular Malformations
PubMed: 33069285
DOI: 10.1016/j.sempedsurg.2020.150974 -
Genetics in Medicine : Official Journal... Oct 2009PTEN hamartoma tumor syndrome (PHTS) encompasses four major clinically distinct syndromes associated with germline mutations in the tumor suppressor PTEN. These allelic... (Review)
Review
PTEN hamartoma tumor syndrome (PHTS) encompasses four major clinically distinct syndromes associated with germline mutations in the tumor suppressor PTEN. These allelic disorders, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome are associated with unregulated cellular proliferation leading to the formation of hamartomas. Thus far, an increased risk of malignancy has only been documented in Cowden syndrome; however, current recommendations advise that all individuals with PTEN hamartoma tumor syndrome follow the cancer surveillance strategies suggested for Cowden syndrome until further data indicate otherwise. Because any individual phenotypic feature of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are frequently present in the general population, many individuals often go undiagnosed and consequently do not benefit from available cancer surveillance strategies. Therefore, it is critical for clinicians to recognize the phenotypic features associated with these syndromes to accurately diagnose and provide preventative care. This overview details the clinical description of the PTEN hamartoma tumor syndrome and associated disorders, their diagnosis and molecular/genetic testing, as well as differential diagnosis for assessment of other hamartoma-associated syndromes.
Topics: Diagnosis, Differential; Genetic Counseling; Hamartoma Syndrome, Multiple; Humans; Molecular Diagnostic Techniques
PubMed: 19668082
DOI: 10.1097/GIM.0b013e3181ac9aea -
Journal of Pediatric Genetics Sep 2015Genetic mosaicism is defined as the presence of two or more genetically distinct cell populations in a single individual. Ever more disorders are found to be... (Review)
Review
Genetic mosaicism is defined as the presence of two or more genetically distinct cell populations in a single individual. Ever more disorders are found to be manifestations of mosaicism and together constitute a significant proportion of the morbidity confronting pediatric specialists. An emerging category is that of overgrowth syndromes with skin manifestations and neurological or developmental abnormalities, such as the well-known Proteus syndrome. In recent years, we have seen dramatic advances in our understanding of these disorders and we now know the genetic basis of many of them. This has profound consequences for diagnosis, counselling, and even treatment, with therapies targeted to specific pathways becoming available for clinical use. Recognizing such overgrowth syndromes, therefore, is more important than ever. Fortunately, their skin manifestations can provide important diagnostic clues when evaluated in the entire phenotypic context. In this review, I provide an overview of the most frequently seen mosaic neurocutaneous phenotypes and discuss their molecular basis.
PubMed: 27617125
DOI: 10.1055/s-0035-1564441 -
American Journal of Human Genetics Apr 2002Germline mutations distributed across the PTEN tumor-suppressor gene have been found to result in a wide spectrum of phenotypic features. Originally shown to be a major... (Review)
Review
Germline mutations distributed across the PTEN tumor-suppressor gene have been found to result in a wide spectrum of phenotypic features. Originally shown to be a major susceptibility gene for both Cowden syndrome (CS), which is characterized by multiple hamartomas and an increased risk of breast, thyroid, and endometrial cancers, and Bannayan-Riley-Ruvalcaba syndrome, which is characterized by lipomatosis, macrocephaly, and speckled penis, the PTEN hamartoma tumor syndrome spectrum has broadened to include Proteus syndrome and Proteus-like syndromes. Exon 5, which encodes the core motif, is a hotspot for mutations likely due to the biology of the protein. PTEN is a major lipid 3-phosphatase, which signals down the PI3 kinase/AKT pro-apoptotic pathway. Furthermore, PTEN is a protein phosphatase, with the ability to dephosphorylate both serine and threonine residues. The protein-phosphatase activity has also been shown to regulate various cell-survival pathways, such as the mitogen-activated kinase (MAPK) pathway. Although it is well established that PTEN's lipid-phosphatase activity, via the PI3K/AKT pathway, mediates growth suppression, there is accumulating evidence that the protein-phosphatase/MAPK pathway is equally important in the mediation of growth arrest and other crucial cellular functions.
Topics: Animals; Disease Models, Animal; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Mice; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases; Phosphoric Monoester Hydrolases; Proteus Syndrome; Signal Transduction; Structure-Activity Relationship; Tumor Suppressor Proteins
PubMed: 11875759
DOI: 10.1086/340026 -
European Review For Medical and... Nov 2023Proteus syndrome (PS) is an extremely rare disorder with ocular manifestations. In this study, we aimed to describe the ophthalmic characteristics and the clinical...
BACKGROUND
Proteus syndrome (PS) is an extremely rare disorder with ocular manifestations. In this study, we aimed to describe the ophthalmic characteristics and the clinical course of an unusual PS patient to acquire a comprehensive and intensive understanding of ocular PS and highlight the importance of collaborative treatment by ophthalmologists.
CASE PRESENTATION
A case of PS with atypical ocular features and syndromes was observed in a Chinese female. Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression. A 1.5-year follow-up showed that the treatment was temporarily effective, but the disease continued to develop. A review of the literature was conducted: forty-eight patients met the inclusion criteria. Although ocular manifestations play important roles in PS diagnosis, only a limited number of cases have been reported to have ocular abnormalities. And to date, almost none of these reports have described the treatment in detail. Therefore, PS patients with ocular manifestations were reviewed.
CONCLUSIONS
PS is a complex disorder with variable characteristics and progressive imbalances. In this paper, the clinical symptoms, molecular characteristics, and differential diagnosis of PS are introduced. More importantly, the ocular manifestations, treatment, and prognosis of PS cases to date are summarized and discussed. This study aimed to acquire a comprehensive and intensive understanding of ocular PS and to reveal the importance of collaborative treatment by ophthalmologists.
Topics: Humans; Female; Proteus Syndrome; Eye
PubMed: 37975355
DOI: 10.26355/eurrev_202311_34306