New Therapeutic Approach in an Infant With Systemic Myofibromatosis and Intestinal Hemorrhage.

We report the case of an infant with multicentric myofibromatosis affecting the gastric and intestinal mucosa, leading to continuous intestinal hemorrhage and iron deficiency. Conventional vinblastine and methotrexate combination treatment was administered for 4 months, but persistent intestinal blood loss required repeated blood transfusions. Because of insufficient tumor response to treatment, we opted for the experimental combination of rapamycin and dasatinib. Six weeks after the start of this therapy, hemoglobin levels stabilized without transfusions, and no fecal blood loss was detected. In addition, a follow-up magnetic resonance imaging excluded tumor progression. We here show the effectiveness of an experimental therapy with rapamycin and dasatinib in a child with multicentric myofibromatosis after the failure of conventional therapy with vinblastine and methotrexate.

Diverse presentation and tailored treatment of infantile myofibromatosis: A single-center experience.

BACKGROUND: Infantile myofibromatosis (IM) is a rare benign fibrous tumor with diverse clinical presentations and treatments, such as watchful waiting, surgical excision, and low-dose chemotherapy. PROCEDURE: Clinical presentation and tailored treatment of five infants with solitary and generalized IM are described, together with a review of the literature. RESULTS: Three patients underwent total-body magnetic resonance imaging (MRI) at diagnosis and during follow up, which revealed disease extension that aided in designing treatment. Visceral involvement included central nervous system, cardiac, gastrointestinal, muscle, bone, and subcutaneous tissue lesions. The patient with the solitary form of IM was followed up without treatment and had spontaneous improvement. Patients with the multicentric form received intravenous low-dose methotrexate and vinblastine chemotherapy. One patient who received oral methotrexate due to cardiac involvement and unfeasible central line access had excellent results. Recurrence was successfully treated by the same methotrexate and vinblastine regimen as that administered at diagnosis. CONCLUSIONS: We suggest screening all patients with one or more IM lesions by means of total body MRI due to its inherent superior soft tissue resolution. Total-body MRI may also be used for routine follow up. Oral methotrexate can be administered successfully in patients that lack central line access, and recurrent lesions can be treated with the same chemotherapeutic combination as that given at diagnosis. Long-term follow up is needed, since recurrence could appear years after initial presentation of the disease.

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy.

More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and late-onset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy and one with a recurrent p.Val665Ala (Penttinen) variant. Along with previously reported individuals, our cohort suggests infants and young children had few abnormal features, while older individuals had multiple additional features, several of which appeared to worsen with advancing age. Our analysis supports a diagnostic entity of a spectrum disorders due to activating variants in PDGFRB. Differences in reported phenotypes can be dramatic and correlate with advancing age, genotype, and to mosaicism in some individuals.

Treatment of generalized infantile myofibromatosis with sorafenib and imatinib: A case report.

Infantile myofibromatosis (IM) is characterized by solitary musculoskeletal nodules presenting during infancy but can manifest as multiple lesions with visceral involvement. Multicentric IM with visceral involvement carries a high risk of mortality and there is no consensus on treatment. We present a case of a patient with multicentric IM and pulmonary involvement who progressed on several chemotherapeutic regimens and subsequently had a complete response to sorafenib and later imatinib. This report describes the novel use of sorafenib and imatinib to treat generalized IM and the role of continued tyrosine kinase inhibitor therapy to maintain remission.

PDGRFB mutation-associated myofibromatosis: Response to targeted therapy with imatinib.

Heterozygous activating mutations in platelet-derived growth factor receptor B (PDGFRB) have been recently identified as a cause of autosomal-dominant infantile myofibromatosis. We describe a 36-year-old man with PDGFRB c.1681C>T (p.R561C) mutation. Upon progressive disease, the patient received treatment with imatinib and showed a remarkable response with remission of multiple lesions after 12 months. This is the first report of an adult patient with PDGFRB c.1681C>T mutation treated with imatinib.

Effects of Sunitinib and Other Kinase Inhibitors on Cells Harboring a PDGFRB Mutation Associated with Infantile Myofibromatosis.

Infantile myofibromatosis represents one of the most common proliferative fibrous tumors of infancy and childhood. More effective treatment is needed for drug-resistant patients, and targeted therapy using specific protein kinase inhibitors could be a promising strategy. To date, several studies have confirmed a connection between the p.R561C mutation in gene encoding platelet-derived growth factor receptor beta (PDGFR-beta) and the development of infantile myofibromatosis. This study aimed to analyze the phosphorylation of important kinases in the NSTS-47 cell line derived from a tumor of a boy with infantile myofibromatosis who harbored the p.R561C mutation in PDGFR-beta. The second aim of this study was to investigate the effects of selected protein kinase inhibitors on cell signaling and the proliferative activity of NSTS-47 cells. We confirmed that this tumor cell line showed very high phosphorylation levels of PDGFR-beta, extracellular signal-regulated kinases (ERK) 1/2 and several other protein kinases. We also observed that PDGFR-beta phosphorylation in tumor cells is reduced by the receptor tyrosine kinase inhibitor sunitinib. In contrast, MAPK/ERK kinases (MEK) 1/2 and ERK1/2 kinases remained constitutively phosphorylated after treatment with sunitinib and other relevant protein kinase inhibitors. Our study showed that sunitinib is a very promising agent that affects the proliferation of tumor cells with a p.R561C mutation in PDGFR-beta.

A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib.

PurposeHeterozygous germ-line activating mutations in PDGFRB cause Kosaki and Penttinen syndromes and myofibromatosis. We describe a 10-year-old child with a germ-line PDGFRB p.N666H mutation who responded to the tyrosine kinase inhibitor imatinib by inhibition of PDGFRB.MethodsThe impact of p.N666H on PDGFRB function and sensitivity to imatinib was studied in cell culture.ResultsCells expressing the p.N666H mutation showed constitutive PDGFRB tyrosine phosphorylation. PDGF-independent proliferation was abolished by imatinib at 1 µM concentration. Patient fibroblasts showed constitutive receptor tyrosine phosphorylation that was also abrogated by imatinib with reduced proliferation of treated cells.This led to patient treatment with imatinib at 400 mg daily (340 mg/m2) for a year with objective improvement of debilitating hand and foot contractures, reduced facial coarseness, and significant improvement in quality of life. New small subcutaneous nodules developed, but remained stable. Transient leukopenia, neutropenia, and fatigue resolved without intervention; however, mildly decreased growth velocity resulted in reducing imatinib dose to 200 mg daily (170 mg/m2). The patient continues treatment with ongoing clinical response.ConclusionTo our knowledge, this is one of the first personalized treatments of a congenital disorder caused by a germ-line PDGF receptor mutation with a PDGFRB inhibitor.

Infantile myofibromatosis

Abstract: 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.

A Rare Case of Infantile Myofibromatosis Presenting to the Emergency Department as Undiagnosed Long Bone Fractures.

Infantile myofibromatosis is a disorder of mesenchymal tumors that usually presents within the first 2 years of life. Most patients initially present because of the presence of visible or palpable subcutaneous tumors. We report a case of a fussy 5-week-old infant who presented to an emergency department with bilateral femur fractures initially thought to be due to nonaccidental trauma or a metabolic bone disorder. She was ultimately diagnosed after admission with infantile myofibromatosis after taking an extensive family history and after further laboratory and radiologic evaluation. There are no previously published cases of undiagnosed infantile myofibromatosis presenting to the emergency department, especially with multiple long bone fractures.

Case report: rapid and durable response to PDGFR targeted therapy in a child with refractory multiple infantile myofibromatosis and a heterozygous germline mutation of the PDGFRB gene.

BACKGROUND: Infantile myofibromatosis belongs to a family of soft tissue tumors. The majority of these tumors have benign behavior but resistant and malignant courses are known, namely in tumors with visceral involvement. The standard of care is surgical resection. Observations suggest that low dose chemotherapy is beneficial. The treatment of resistant or relapsed patients with multifocal disease remains challenging. Patients that harbor an actionable mutation in the kinase domain are potential subjects for targeted tyrosine kinase inhibitor therapy. CASE PRESENTATION: An infant boy with inborn generalized infantile myofibromatosis that included bone, intracranial, soft tissue and visceral involvement was treated according to recent recommendations with low dose chemotherapy. The presence of a partial but temporary response led to a second line of treatment with six cycles of chemotherapy, which achieved a partial response again but was followed by severe toxicity. The generalized progression of the disease was observed later. Genetic analyses were performed and revealed a PDGFRB gene c.1681C>A missense heterozygous germline mutation, high PDGFRß phosphokinase activity within the tumor and the heterozygous germline Slavic Nijmegen breakage syndrome 657del5 mutation in the NBN gene. Targeted treatment with sunitinib, the PDGFRß inhibitor, plus low dose vinblastine led to an unexpected and durable response without toxicities or limitations to daily life activities. The presence of the Slavic NBN gene mutation limited standard chemotherapy dosing due to severe toxicities. Sister of the patient suffred from skull base tumor with same genotype and histology. The same targeted therapy led to similar quick and durable response. CONCLUSION: Progressive and resistant incurable infantile myofibromatosis can be successfully treated with the new approach described herein. Detailed insights into the biology of the patient's tumor and genome are necessary to understand the mechanisms of activity of less toxic and effective drugs except for up to date population-based chemotherapy regimens.

Infantile myofibromatosis.

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.

Vincristine and Dactinomycin in Infantile Myofibromatosis With a Review of Treatment Options.

Although solitary presentations of infantile myofibromatosis tend toward spontaneous regression, multicentric forms fare worse. Previous case reports have depicted observation, surgical resection, and systemic therapies as treatment options. This paper reports well-tolerated, successful outcomes in a series of patients with high-risk infantile myofibromatosis in need of life-sustaining interventions treated with a combination of vincristine and dactinomycin. The clinical presentation, pathology, and radiographic findings are described.

Chemotherapy for Generalized Infantile Myofibromatosis With Visceral Involvement.

Infantile myofibromatosis (IM) is most commonly limited to cutaneous lesions that resolve spontaneously. However, generalized IM with visceral involvement, which has a reported mortality rate as high as 73%, has been successfully treated with a combination of methotrexate and vinblastine. Here we report the further efficacy of low-dose methotrexate and vinblastine in 2 pediatric patients with IM and visceral involvement and review the literature describing chemotherapy for these patients.

Infantile myofibromatosis: report on a family with autosomal dominant inheritance and variable penetrance.

Infantile myofibromatosis (IM) is a benign tumor occurring in infants and young children. Familial IM is rare and the inheritance pattern of IM is unclear. We report on a unique family with four individuals having IM of varying degrees of severity with autosomal dominant inheritance pattern and variable penetrance.

Mesenteric myofibroblastic tumor: NSAID therapy after incomplete resection.

Myofibroblastic tumors are inflammatory tumors that arise in viscera and soft tissue; their etiopathology is poorly understood. They are capable of infiltration of adjacent organs, local recurrence after surgical resection, and even of distant metastasis. These characteristics result in persistent debate as to the nature of these lesions - whether they are inflammatory or neoplastic, benign or malignant lesions? Diagnosis is almost always made based on histopathological findings. Traditional management is complete surgical excision, but this may be difficult or impossible when the lesion develops in proximity to vital structures. We report the case of a 59-year-old man who was treated in our institution for mesenteric myofibroblastic tumor. Complete resection was not possible due to local infiltration of the mesentery. Recurrence was noted 3 months after surgery; treatment with steroidal and then non-steroidal anti-inflammatory medications (NSAIDs) resulted in clinical and radiologic regression of the tumor.

Development of renal and iliac aneurysms in a child with generalized infantile myofibromatosis.

Infantile myofibromatosis is a rare disorder characterized by the formation of tumors in the skin, soft tissues, bone, and viscera. We report the case of a 3-week-old girl who presented with severe hypertension due to generalized infantile myofibromatosis including renal involvement. The infant was treated by chemotherapy and showed progressive regression of the tumors. However, her evolution was marked by the development of aneurismal dilations of the renal and iliac arteries as observed in fibromuscular dysplasia. We discuss the possibility of a link between these two mesenchymal disorders.