Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group
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ORIGINAL ARTICLE
Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group Simone Hettmer1 · Guillaume Dachy2 · Guido Seitz3 · Abbas Agaimy4 · Catriona Duncan5 · Marjolijn Jongmans6,7 · Steffen Hirsch8,9 · Iris Kventsel10 · Uwe Kordes11 · Ronald R. de Krijger6,12 · Markus Metzler13 · Orli Michaeli14 · Karolina Nemes15 · Anna Poluha16,17 · Tim Ripperger18 · Alexandra Russo19 · Stephanie Smetsers6 · Monika Sparber‑Sauer20 · Eveline Stutz21 · Franck Bourdeaut22 · Christian P. Kratz23 · Jean‑Baptiste Demoulin2 Received: 17 June 2020 / Accepted: 19 August 2020 © The Author(s) 2020
Abstract Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variants. Somatic PDGFRB variants were also detected in solitary and multifocal IM lesions. PDGFRB variants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRB germline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations. Keywords Infantile myofibromatosis · PDGFRB variants · Genetic counseling · Surveillance
Introduction
Clinical case presentation
Infantile myofibromatosis/myofibromas (IM) were first described by Stout in 1954 as congenital generalized fibromatosis [1]. Disease manifestations range from solitary soft tissue nodules (infantile myofibromas) to multiple or disseminated (generalized) tumors (infantile myofibromatosis) with life-threatening complications, particularly if visceral disease is present. Most IM cases are diagnosed in children below 2 years of age. The reported incidence of IM is 1 in 150,000 live births, but, as minor forms of the disease may go unnoticed, the true incidence of IM is likely much higher [2].
A female infant, born at 38 + 3 weeks gestation by vaginal delivery to a 27 year-old healthy mother, presented with a large round mass on the left forefoot and a 9 mm red-colored lesion on the lateral aspect of the right hand at birth (Fig. 1a, b). Prenatal screening had not revealed any anomalies. Whole body MRI was carried out on day of life 4 and demonstrated contrast-enhancing lesions in the chest (2.6 × 2.4 × 1.4 cm, located in the left paracardial regio
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