What is Infantile Myofibromatosis?

Infantile myofibromatosis (IM), despite being a rare disease, is the most common musculoskeletal soft-tissue tumour presenting at infancy.¹ Around one infant out of 150,000 live births is affected by this condition.² IM is a mesenchymal condition, which means that it affects the connective tissues of the body, including bone, ligaments, and cartilage. It creates proliferations and tumours or large bumps on the skin, muscles, and other areas. These discrete nodules or lesions are characteristic of IM (Figure 1).³

*Figure 1: The lesions characteristic to infantile myofibromatosis, on the right shoulder. This image may be disturbing for some viewers.*

There are different types of IM, each with a different presentation and mortality rate; the different types include solitary, multicentric, and multicentric with visceral involvement. Solitary IM represents around 75% of the cases, and involves only one lesion, usually in the skin. Multicentric IM involves multiple lesions and affected areas. These first two types usually have a good prognosis and very low mortality rates. In contrast, multicentric IM with visceral involvement affects internal organs as well, such as the lungs, heart, and gastrointestinal tract. ¹ It is the most severe and life-threatening type, with a mortality rate of 80%. ⁴

Despite the implications of this third type of IM, there is currently no consensus on its treatment. Efforts were originally made to reduce the tumours or lesions that present with the illness, which are normally treated using chemotherapy. However, chemotherapeutic agents have been found to have little success in treating IM; the cause behind this is not clearly known. ⁴ New research on how to treat IM and manage the disease over a long period of time will be discussed below.

Genetic Basis

Most of the past research conducted towards this disease focuses on clinical findings and the diagnosis of infantile myofibromatosis. Recently, several findings on the genetic basis of IM have also been discovered, leading to new evidence that can be used to treat the condition. ³

IM has been found to present with both autosomal-recessive and autosomal-dominant patterns. After whole-exome sequencing (sequencing all the coding genes in an organism’s DNA) of IM patients, or patients who had family members with IM, it was found that the disease involves mutations on specific chromosomes. ⁵ The particular mutations can be found on the platelet-derived growth factor receptor β (PDGFRB) gene and the neurogenic locus notch homolog 3 (NOTCH3) gene, which is found on chromosome 19. ^6,7 Missense mutations on both of these genes are suspected to cause infantile myofibromatosis. A missense mutation causes a defect in certain proteins produced by the body, and hinders their function. ⁷

The two genes, PDGFRB and NOTCH3, are associated with tyrosine kinase receptors (Figure 2). ⁸ These are a very common type of receptor that use the amino acid tyrosine to carry signals into the cell. The fact that these genes are associated with this receptor is important to the discovery of treatments of IM. When a genetic factor of a disease is known, researchers can investigate what molecules or mutations are involved, and take further steps towards treating the condition. However, the exact relationship between the receptors and the pathophysiology of the lesions still remains unknown. ⁷

*Figure 2: Protein structure of a tyrosine kinase receptor.*

Past Research and Knowledge

Past research on IM usually focuses on clinical findings, such as the prognosis and remission of the disease. Additionally, these studies describe the characteristic tumours in detail, along with their cystic spaces that are often filled with hemorrhagic material.^3,9 When the gastrointestinal tract also has these tumours, polyploid or ulcerated growth is seen, meaning that the tumour cells have too many chromosomes and they can grow through the tract tissue. If these tumours are found in the lungs, the morbidity and mortality rate can be particularly high.³ The histology of the lesions show tapered cell lobes that appear to be similar to smooth muscle cells and fibroblasts. In terms of immunohistochemistry, both the type III intermediate filament vimentin and smooth muscle actin have been found to be characteristic of IM (Figure 3). Immunohistochemistry is the study of what proteins are found in a given sample of tissue, and can help researchers understand what is being produced in the IM tumouts.³

*Figure 3: Microscopy imaging of the spindle-cell proliferation inside the lesions.*

The past treatment of infantile myofibromatosis has involved surgical incisions that take out the tumours, although they can recur, and chemotherapy with a variety of common agents. However, the results for these treatments have been largely unsuccessful, signifying the importance of new research.

Current Research and New Findings

New research has recently been conducted investigating the use of sorafenib (Figure 4) and imatinib as treatments for IM (Figure 5). ⁴

Sorafenib and imatinib were found to inhibit mutated tyrosine kinase receptors, and the mutated PDGFRB receptors were inhibited by imatinib in in vitro trials. In the original study, a female infant with no family history of IM was found with several, sometimes recurring, lesions. Originally, treatment with commonly used chemotherapeutic agents was conducted. Specifically, these agents included vinblastine and methotrexate, and they were later replaced with vincristine, dactinomycin, and cyclophosphamide. ⁴

Despite this therapy, little success was found in reducing tumours. The subject was given sorafenib regularly, and the lesions became smaller with side-effects of diarrhea and eczema. After the lesions and symptoms of IM were resolved, sorafenib dosages were stopped. However, the lesions recurred quickly after sorafenib was not administered. To avoid the side-effects of diarrhea and eczema, imatinib was used for treatment instead. Again, the lesions disappeared when imatinib was regularly administered, but when treatment was stopped, they recurred. The cause behind this recurrence is still unclear. ⁴

The subject was hence regularly given imatinib to prevent lesions without the side effects that sorafenib presented. The study shows that because PDGFRB is a tyrosine kinase receptor coding gene, the use of imatinib and sorafenib counteract any mutations, since both are inhibitors of mutated tyrosine kinase receptors. ⁴ The current research hence shows that chemotherapy and surgery are unsuccessful in treating IM, while the disease responds rapidly to the two agents mentioned. The new study that took place is crucial, as it presents a targeted therapy to a rare disease with a high mortality rate and lack of promising treatments. ⁴

Conclusion

The future directions of this study are promising, as they present a potential therapy for infantile myofibromatosis. The use of chemotherapy and surgery for this disease is refuted, and sorafenib and imatinib may now be researched further as suitable therapeutic drugs. Reduction of their side-effects should be researched to avoid complications during the dosages. Furthermore, the implications that the study has for understanding tyrosine kinase receptors is significant. It presents new insights into how these components of cell signalling operate, and whether more can be found from studying IM. More research would be needed, using double-blinded trials with larger sample sizes, to further investigate both sorafenib and imatinib. The study of both the receptors and their inhibitors may advance the treatments of infantile myofibromatosis.

Ayesha Umair

Works Cited

National Organization for Rare Disorders. NORD. 2020. https://rarediseases.org/rare-diseases/infantile-myofibromatosis/.
Genetic and Rare Diseases Information Center. National Center for Advancing Translational Sciences. 2019. https://rarediseases.info.nih.gov/diseases/2998/infantile-myofibromatosis.
Larralde M, Bruno F, Martinez JP, Barbieri MF, Méndez JH, Casas J. Infantile myofibromatosis. Anais Brasileiros de Dermatologia. 2017;92(6):854-857. doi:10.1590/abd1806-4841.20175001.
Bidadi B, Watson A, Weigel B, Oliveira A, Kirkham J, Arndt C. Treatment of generalized infantile myofibromatosis with sorafenib and imatinib: A case report. Pediatric Blood & Cancer. 2020;67(6):e28288. doi:10.1002/pbc.28288.
Martignetti JA, Tian L, Dong L, Ramirez MC, Camacho-Vanegas O, Camacho S, Guo Y, Zand DJ, Bernstein AM, Masur SK, Kim CE, Otieno FG, Hou C, Abdel-Magid N, Tweddale B, Metry D, Fournet J, Papp E, McPherson EW, … Hakonarson H. Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis. The American Journal of Human Genetics. 2013;92(6):1001-1007. doi:10.1016/j.ajhg.2013.04.024.
Arts FA, Chand D, Pecquet C, Velgh AI, Constantinescu S, Hallberg B & Demoulin JB. PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. Oncogene. 2016;35:3239-3248. doi:10.1038/onc.2015.383.
Cheung YH, Gayden T, Campeau, LeDuc CA, Russo D, Nguyen V, Guo J, Guan Y, Albrecht S, Moroz B, Eldin KW, Lu JT, Schwartzentruber J, Malkin D, Berghuis AM, Emil S, Gibbs RA, Burk D, … Jabado N. A Recurrent PDGFRB Mutation Causes Familial Infantile Myofibromatosis. The American Journal of Human Genetics. 2013;92(6):996-1000. doi: 10.1016/j.ajhg.2013.04.026.
Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J. Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor. Cell. 2007;130(2):323-334. doi: 10.1016/j.cell.2007.05.055.
Chung EB, Enzinger FM. Infantile myofibromatosis. Cancer. 1981;48(8):1807-1818. doi:10.1002/1097-0142(19811015)48:8<1807::AID data-preserve-html-node="true" data-preserve-html-node="true"-CNCR2820480818>3.0.CO;2-G.

Cite This Article:

Umair A., Bhansali M., Pham E. New Treatments for Infantile Myofibromatosis. Illustrated by S. Chen. Rare Disease Review. February 2021. DOI: 10.13140/RG.2.2.25838.54083