UNASSIGNED: To investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis.
UNASSIGNED: Case series with genetic and functional in vitro analyses.
UNASSIGNED: Four individuals from 2 unrelated families with clinical signs of corneal myofibromatosis were investigated.
UNASSIGNED: Exome-based panel sequencing for platelet-derived growth factor receptor beta gene (PDGFRB) and notch homolog protein 3 gene (NOTCH3) was performed in the respective index patients. One clinically affected member of each family was tested for the pathogenic variant detected in the respective index by Sanger sequencing. Immunohistochemical staining on excised corneal tissue was conducted. Functional analysis of the individual PDGFRB variants was performed in vitro by luciferase reporter assays on transfected porcine aortic endothelial cells using tyrosine kinase inhibitors. Protein expression analysis of mutated PDGFRB was analyzed by Western blot.
UNASSIGNED: Sequencing data, immunohistochemical stainings, functional analysis of PDGFRB variants, and protein expression analysis.
UNASSIGNED: We identified 2 novel, heterozygous gain-of-function variants in PDGFRB in 4 individuals from 2 unrelated families with corneal myofibromatosis. Immunohistochemistry demonstrated positivity for alpha-smooth muscle actin and β-catenin, a low proliferation rate in Ki-67 (< 5%), marginal positivity for Desmin, and negative staining for Caldesmon and CD34. In all patients, recurrence of disease occurred after corneal surgery. When transfected in cultured cells, the PDGFRB variants conferred a constitutive activity to the receptor in the absence of its ligand and were sensitive to the tyrosine kinase inhibitor imatinib. The variants can both be classified as likely pathogenic regarding the American College of Medical Genetics and Genomics classification criteria.
UNASSIGNED: We describe 4 cases of corneal myofibromatosis caused by novel PDGFRB variants with autosomal dominant transmission. Imatinib sensitivity in vitro suggests perspectives for targeted therapy preventing recurrences in the future.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Infantile myofibromatosis (IM) is a rare disorder characterized by the formation of nodules in the skin, muscle, bone, and, more rarely, visceral organs. Very few cases are detected prenatally, and the final diagnosis cannot be made until pathology is completed after birth. Here, we present a case of disseminated form IM (DFIM) with a diagnosis established on prenatal genetic grounds.
A woman at 23 weeks of gestation was referred for ultrasound evaluation of fetal kidney abnormality. Generalized masses in the skin and muscle of the fetus developed at 28 weeks. Prenatal genetic testing identified the pathogenic heterozygous variant c.1681C > T (p.R561C) of the PDGFRB gene inherited from the asymptomatic father. Intrauterine demise occurred at 31 weeks. Autopsy confirmed DFIM with involvement of the heart and kidney. All cases of prenatally detected IM were reviewed, revealing an association of high mortality with DFIM.
Prenatal IM diagnosis is difficult. Initial detection is always based on ultrasound. DFIM has high mortality. The germline p.R561C mutation in PDGFRB may cause fetal demise due to severe visceral involvement of IM. Prenatal genetic testing provides a diagnosis before pathological results are available, leading to better counseling and management of pregnancy with a fetus with IM.

Infantile myofibromatosis (IM) is the most common fibrous disorder of infancy and early childhood. Solitary intracranial involvement is rare and often unrecognized. This makes its early diagnosis and adequate management difficult. The majority of lesions are localized to the skull or dura with variable intracranial extension. Herein, we report a misdiagnosed and aggressive presentation of a solitary IM of the petrous bone. Our aim is to discuss histopathological differential diagnoses and management difficulties.

Describe a novel use for a kinase inhibitor, imatinib, in young children with a known activated somatic mutation in PDGFR-beta. Two patients with infantile myofibromatosis treated with imatinib. Case description of evaluation, diagnosis and treatment decisions for infantile myfibromatosis of the head and neck. Description of medical therapy for infantile myofibromatosis in these patients. For function threatening myofibromas of a known genotype, in infants, targeted medical therapy is a treatment option.

BACKGROUND: Infantile myofibromatosis (IM) is a soft tissue disease with solitary or multiple benign tumors, and an etiology still unknown. IM is a mesenchymal disorder of early infancy and is more frequent in males. IM may present as a solitary lesion of the skin, bone, muscle, subcutaneous tissue, located at the head, neck, and trunk, with good prognosis; or, as a multicentric form, with or without visceral involvement (heart, lung, gastrointestinal tract, kidney), with a poor prognosis. The definitive diagnosis of IM is confirmed by pathology. Treatment may be conservative, surgical, or chemotherapeutical.
METHODS: A two months old female patient, prenatally diagnosed at 30 weeks, presenting with a tumor on the antero-internal aspect of the left thigh. She was admitted due to rapid postnatal evolution, and the patient required surgery for tumor resection. Previously, clinically, biological and imaging investigations were performed, but the final diagnosis was histological and by immunostaining. The patient had a favorable postoperative outcome.
CONCLUSIONS: Despite its low frequency, IM should be considered in the differential diagnosis of soft tissue masses at an early age. The clinical form (solitary or multicentric), location, and visceral involvement will dictate the treatment and prognosis.

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of infancy, characterized by the development of single or multiple nodules in the skin, soft tissues, bone, and/or viscera. Multicentric forms are less frequent and can affect different tissues simultaneously and their prognosis depends on their extension and visceral involvement. Rarely, these forms are limited to the skeleton, in which case the absence of extraosseous lesions makes it difficult to suspect this entity. We present the case of an infant with multiple radiolucent lesions involving the skull, ribs, spine, and long bones, discovered in a radiological study performed after a minor trauma. A broad differential diagnosis was considered based on the osteolytic and polyostotic nature of the lesions on imaging studies. This report details and illustrates the typical radiological findings in bony involvement of IM, which suggest this disorder over other diagnostic options.

BACKGROUND: Infantile myofibromatosis (IM) is a rare benign soft tissue tumor and often a self-limiting disease but rarely includes life-threatening complications. Little is known about optimal treatment of primary localized (LD) and multifocal disease (MFD).
METHODS: Treatment and outcome of 95 children with IM registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2016) were evaluated.
RESULTS: LD was diagnosed in 71 patients at a median age of 0.4 years (range 0.0-17.7). MFD was present in 24 patients. The mainstay of treatment was watch-and-wait strategy (w&w) after initial biopsy or resection. Low-dose chemotherapy (CHT) was administered to 16/71 (23%) patients with LD and eight of 24 (33%) patients with MFD, imatinib was added in two. A delayed resection was possible in eight of 71 (11%) and five of 24 (21%) patients with LD and MFD, respectively. Overall, patients were alive in complete remission (n = 77) and partial remission (n = 10) at a median follow-up time of 3.4 years after diagnosis (range 0.01-19.4); no data available (n = 5). Three patients died of progressive disease (PD) despite CHT. Gender, tumor size, and location correlated with a favorable event-free survival (EFS) in patients with LD. The 5-year EFS and overall survival of patients with LD were 73% (±12, confidence interval [CI] 95%) and 95% (±6, CI 95%), respectively; for MFD 51% (±22, CI 95%) and 95% (±10, CI 95%).
CONCLUSIONS: Prognosis is excellent in patients with LD and MFD. Targeted treatment needs to be evaluated for rare fatal PD.

Multiple papulonodular skin lesions at birth can indicate the presence of various benign and malignant disorders. Although the lesions\' clinical aspect (color and consistency, in particular) may steer the clinician towards one disorder or another (infantile myofibromatosis, xanthogranuloma, or metastatic neuroblastoma), the diagnosis can only be confirmed by the histopathologic assessment of a biopsy. In neonates, a rapid but accurate diagnosis is critical because skin lesions may be the first manifestation of a malignant disorder like leukemia cutis or metastatic neuroblastoma. Here, we review the various disorders that may manifest themselves as multiple skin lesions at birth.

Infantile myofibromatosis is a rare and nonmalignant pediatric tumor of myofibroblastic origin that may occur in solitary or multifocal forms. Soft tissue of the head and neck, trunk, and extremities, skeleton, and viscera are usually involved. Intracranial involvement is reported to be extremely rare, and its clinical picture has been poorly characterized. We present two cases of giant infantile myofibromatosis of the skull base with intracranial involvement. The first case with prenatal diagnosis involved extensively the extradural space of the occipital region and was previously treated by chemotherapy for a previous diagnosis of hemangioperycitoma. Tumor was removed at the age of 5 months and no recurrence was observed during the 3-year follow-up. The second case in a 2-year-old baby involved the anterior cranial base, the nasal cavity, the right orbit, and presented massive involvement of the anterior cranial fossa. Surgery allowed complete removal and a recurrence-free period of 7 years after surgery. Treatment options for these unusual cases are presented and details of histological diagnosis are discussed.

BACKGROUND: Infantile myofibromatosis (IM) is the most common cause of multiple fibrous tumors in infancy. Multicentric disease can be associated with life-threatening visceral lesions. Germline gain-of-function mutations in PDGFRB have been identified as the most common molecular defect in familial IM.
METHODS: We here describe an infant with PDGFRB-driven IM with multiple tumors at different sites, including intestinal polyposis with hematochezia, necessitating temporary chemotherapy.
CONCLUSIONS: PDGFRB-driven IM is clinically challenging due to its fluctuating course and multiple organ involvement in the first years of life. Early molecular genetic analysis is necessary to consider tyrosine kinase inhibitor treatment in case of aggressive visceral lesions.