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Cellular and Molecular Life Sciences :... Apr 2021PDGFRA and PDGFRB are classical proto-oncogenes that encode receptor tyrosine kinases responding to platelet-derived growth factor (PDGF). PDGFRA mutations are found in... (Review)
Review
PDGFRA and PDGFRB are classical proto-oncogenes that encode receptor tyrosine kinases responding to platelet-derived growth factor (PDGF). PDGFRA mutations are found in gastrointestinal stromal tumors (GISTs), inflammatory fibroid polyps and gliomas, and PDGFRB mutations drive myofibroma development. In addition, chromosomal rearrangement of either gene causes myeloid neoplasms associated with hypereosinophilia. Recently, mutations in PDGFRB were linked to several noncancerous diseases. Germline heterozygous variants that reduce receptor activity have been identified in primary familial brain calcification, whereas gain-of-function mutants are present in patients with fusiform aneurysms, Kosaki overgrowth syndrome or Penttinen premature aging syndrome. Functional analysis of these variants has led to the preclinical validation of tyrosine kinase inhibitors targeting PDGF receptors, such as imatinib, as a treatment for some of these conditions. This review summarizes the rapidly expanding knowledge in this field.
Topics: Animals; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Intestinal Polyps; Mutation; Myofibromatosis; Receptors, Platelet-Derived Growth Factor
PubMed: 33449152
DOI: 10.1007/s00018-020-03753-y -
Anais Brasileiros de Dermatologia 2017Infantile myofibromatosis is a mesenchymal disorder characterized by the fibrous proliferation of the skin, bone, muscle and viscera. It is the most common fibrous tumor...
Infantile myofibromatosis is a mesenchymal disorder characterized by the fibrous proliferation of the skin, bone, muscle and viscera. It is the most common fibrous tumor in childhood. We present a newborn with skin and bone disease without visceral involvement, who showed good response to vinblastine and methotrexate. Clinical features, etiology, diagnosis, and treatment are reviewed.
Topics: Dermatologic Agents; Humans; Immunohistochemistry; Infant, Newborn; Male; Methotrexate; Myofibromatosis; Treatment Outcome; Vinblastine
PubMed: 29364448
DOI: 10.1590/abd1806-4841.20175001 -
Fibroblastic and myofibroblastic tumors of children: new genetic entities and new ancillary testing.F1000Research 2018Fibroblastic and myofibroblastic tumors comprise a morphologically diverse and biologically variable group of neoplasms that affect a wide age range. Specific entities... (Review)
Review
Fibroblastic and myofibroblastic tumors comprise a morphologically diverse and biologically variable group of neoplasms that affect a wide age range. Specific entities tend to occur most frequently in infants and young children. Recent years have witnessed a proliferation of information concerning the unique biology of these tumors. In this report, I will review recent findings that serve to further characterize this group of neoplasms. Included will be newer information on fibrous hamartoma of infancy, infantile myofibromatosis, lipofibromatosis, and infantile fibrosarcoma and tumors resembling it, including primitive myxoid mesenchymal tumor of infancy and new genetic entities. I will also discuss the differential diagnosis, which includes spindle cell rhabdomyosarcoma, dermatofibrosarcoma protuberans, and calcifying aponeurotic fibroma.
Topics: Adolescent; Child; Child, Preschool; Diagnosis, Differential; Fibroblasts; Humans; Neoplasms, Connective and Soft Tissue; Neoplasms, Fibrous Tissue
PubMed: 30613391
DOI: 10.12688/f1000research.16236.1 -
Journal of Cellular and Molecular... Jul 2022Penttinen syndrome is a rare progeroid disorder caused by mutations in platelet-derived growth factor (PDGF) receptor beta (encoded by the PDGFRB proto-oncogene) and...
Penttinen syndrome is a rare progeroid disorder caused by mutations in platelet-derived growth factor (PDGF) receptor beta (encoded by the PDGFRB proto-oncogene) and characterized by a prematurely aged appearance with lipoatrophy, skin lesions, thin hair and acro-osteolysis. Activating mutations in PDGFRB have been associated with other human diseases, including Kosaki overgrowth syndrome, infantile myofibromatosis, fusiform aneurysms, acute lymphoblastic leukaemia and myeloproliferative neoplasms associated with eosinophilia. The goal of the present study was to characterize the PDGFRB p.Val665Ala variant associated with Penttinen syndrome at the molecular level. This substitution is located in a conserved loop of the receptor tyrosine kinase domain. We observed that the mutant receptor was expressed at a lower level but showed constitutive activity. In the absence of ligand, the mutant activated STAT1 and elicited an interferon-like transcriptional response. Phosphorylation of STAT3, STAT5, AKT and phospholipase Cγ was weak or undetectable. It was devoid of oncogenic activity in two cell proliferation assays, contrasting with classical PDGF receptor oncogenic mutants. STAT1 activation was not sensitive to ruxolitinib and did not rely on interferon-JAK2 signalling. Another tyrosine kinase inhibitor, imatinib, blocked signalling by the p.Val665Ala variant at a higher concentration compared with the wild-type receptor. Importantly, this concentration remained in the therapeutic range. Dasatinib, nilotinib and ponatinib also inhibited the mutant receptor. In conclusion, the p.Val665Ala variant confers unique features to PDGF receptor β compared with other characterized gain-of-function mutants, which may in part explain the particular set of symptoms associated with Penttinen syndrome.
Topics: Acro-Osteolysis; Aged; Humans; Interferons; Limb Deformities, Congenital; Myofibromatosis; Progeria; Receptor, Platelet-Derived Growth Factor beta; STAT1 Transcription Factor
PubMed: 35689379
DOI: 10.1111/jcmm.17427 -
Journal of Otolaryngology - Head & Neck... Mar 2019Infantile myofibromatosis is the most common benign fibrous tumor in infants. Three different types have been reported in the literature. The most commonly affected...
BACKGROUND
Infantile myofibromatosis is the most common benign fibrous tumor in infants. Three different types have been reported in the literature. The most commonly affected areas are the head, the neck and the trunk. Our patient showed a very high level of mandibular destruction resistant to all mandibular sparing treatment strategies requiring segmental mandibulectomy and complex reconstruction.
CASE PRESENTATION
We describe a rare case of multicentric infantile myofibromatosis with mandibular bone destruction. The treatment required a succession of chemotherapy, a subtotal transoral resection and a hemi-mandibulectomy. The mandibular reconstruction was staged with initial bridging titanium plate with a submental flap, followed later by a fibula free flap.
CONCLUSION
Mandibular involvement by myofibromatosis is rare, and the extend of bone destruction and reconstruction make this case unique. To our knowledge, this is the only reported case of fibula free flap mandibular reconstruction in a patient with infantile myofibromatosis , as well as one of the youngest reported submental island flaps for any pathology. We describe the clinical presentation and management, including relevant imaging, histopathology, medical and surgical treatment as well as a review of relevant literature.
Topics: Free Tissue Flaps; Humans; Infant; Male; Mandibular Osteotomy; Mandibular Reconstruction; Myofibromatosis; Plastic Surgery Procedures
PubMed: 30871614
DOI: 10.1186/s40463-019-0333-z -
The Medical Journal of Malaysia Dec 2001Infantile myofibromatosis (IMF) is a rare tumour with a wide spectrum of disease activity ranging from a solitary cutaneous nodule through to a multicentric form with...
Infantile myofibromatosis (IMF) is a rare tumour with a wide spectrum of disease activity ranging from a solitary cutaneous nodule through to a multicentric form with widespread visceral involvement. It is characterised by its unique ability to spontaneously regress and has a typical histological appearance of actin-positive fibroblasts arranged in whorls or fascicles and vessels in a pericytomatous pattern. A male infant with multiple lesions involving the subcutaneous tissue and bone from birth is described and followed-up for two years. Treatment of IMF is dependent on the location of the tumour/s with surgery or chemotherapy reserved for rapidly progressive or symptomatic disease. However, due to the low rate of recurrence and the possibility of spontaneous tumoral regression, therapeutic abstention, as practised in our patient, is justified.
Topics: Humans; Infant; Infant, Newborn; Male; Myofibromatosis
PubMed: 12014771
DOI: No ID Found -
Modern Pathology : An Official Journal... May 2023PDGFRB-activating mutations have been reported in pediatric myofibroma and myofibromatosis. However, recurrent gain-of-function PDGFRB mutations have not been documented...
PDGFRB-activating mutations have been reported in pediatric myofibroma and myofibromatosis. However, recurrent gain-of-function PDGFRB mutations have not been documented in sarcomas with myogenic differentiation. Driven by occasional sarcomas harboring PDGFRB mutations, we investigated their prevalence and clinicopathologic and genomic features in a large cohort of sarcomas. An institutional targeted DNA next-generation sequencing database was searched for sarcomas with myogenic differentiation harboring hotspot PDGFRB gene alterations. Among 3300 patients with sarcomas, 21 (0.6%) patients were identified (17 women, 4 men) with an age range of 35 to 88 years. The site distribution included 13 gynecologic tract (12 uteri, 1 vagina), 4 bone and soft tissue, and 4 viscera. All except 1 were high grade. Most patients were diagnosed as sarcomas with myogenic differentiation based on partial staining for 1 or more muscle markers, whereas 6 were labeled as leiomyosarcoma (LMS). Most tumors showed monomorphic spindle morphology, with either heterogeneous features of myofibroblastic and smooth muscle differentiation or an undifferentiated phenotype. Hormone receptors were negative in all uterine cases. PDGFRB immunostaining in all cases tested was strong and diffuse, whereas PDGFRA was negative/focal. The most frequent PDGFRB mutations were exon 12 (43%), exon 14 (N666K/S/T) (38%), and exon 18 (D850Y/H/V or insertion/deletion) (19%). The most frequent co-existing genetic alterations (26% to 37%) occurred in CDKN2A/B, TP53, TERT, and MED12. Moreover, PDGFRB-mutant sarcomas had an overall distinct genomic landscape compared with both uterine and soft tissue LMS control groups. These tumors were associated with a highly aggressive clinical course, with frequent distant metastases (81%) and death (76%), regardless of anatomic location, and worse overall survival compared with the 2 LMS control groups. This is the first study documenting recurrent hotspot PDGFRB alterations in high-grade sarcomas, which show a predilection for uterine location and myogenic differentiation that fall short of the diagnostic criteria for LMS. Further studies are needed to investigate the therapeutic potential of kinase inhibitors in this group of tumors.
Topics: Humans; Female; Receptor, Platelet-Derived Growth Factor beta; Sarcoma; Leiomyosarcoma; Mutation; Soft Tissue Neoplasms
PubMed: 36788091
DOI: 10.1016/j.modpat.2023.100104 -
BMC Medical Imaging Aug 2020The aim of this study was to characterize the radiological features of myofibroma on multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) and...
BACKGROUND
The aim of this study was to characterize the radiological features of myofibroma on multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) and correlate the imaging findings with pathologic features.
METHODS
The radiological findings of 24 patients with 29 myofibromas were retrospectively reviewed. All images were evaluated with emphasis on density, signal intensity, hypointense area, and enhancement, correlating these with pathologic findings.
RESULTS
On plain MDCT scan, 4(26.7%) tumors were homogeneous isodensity, 4(26.7%) tumors were heterogeneous hyperdensity, and 7(46.7%) tumors were heterogeneous hypodensity. On contrast-enhanced MDCT scan, all tumors (9/9) showed heterogeneous enhancement with moderate in 3(33.3%) and marked in 6(66.7%) tumors, and their enhancements were higher compared to adjacent skeletal muscle (P = 0.0001). On MRI, heterogeneous slight hyperintensity, homogeneous slight hyperintensity, and heterogeneous hypointensity on T1-weighted imaging (T1WI) were observed in 14(82.3%), 1(5.9%) and 2(11.8%) tumors, respectively. On T2-weighted imaging (T2WI) and fat-suppressed (FS) T2WI, all tumors demonstrated heterogeneous hyperintensity. All tumors showed heterogeneous marked enhancement on FS contrast-enhanced T1WI. On T1WI, T2WI, FS T2WI, and FS contrast-enhanced T1WI, irregular strip or/and patchy hypointensities were found in 16(94.1%), 12(100%), 17(100%) and 17(100%) tumors, respectively, and pseudocapsule was seen in 5(29.4%) tumors. The hypointensities and pseudocapsule on MRI were exactly corresponding to pathological interlacing collagen fibers and fibrosis. The age of the recurrent group was lower than that of the non-recurrent group (P = 0.001) and the tumors without pseudocapsule were more likely to recur than those with pseudocapsule (P = 0.034).
CONCLUSION
Myofibromas are characterized by heterogeneous density or signal intensity, with moderate or marked enhancement. The hypointensities and pseudocapsule on MRI may be helpful in diagnosis, and the absence of pseudocapsule and younger age may be risk factors for tumor recurrence.
Topics: Adolescent; Adult; Age Factors; Child; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multidetector Computed Tomography; Myofibroma; Myofibromatosis; Retrospective Studies; Young Adult
PubMed: 32847537
DOI: 10.1186/s12880-020-00498-9