Last updated:
7/23/2024
Years published: 1990, 1993, 1996, 2001, 2002, 2014, 2017, 2020, 2024
NORD gratefully acknowledges Todor Arsov, MD, PhD, Department of Pediatrics Columbia University and Wendy K. Chung, MD, PhD, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, for assistance in the preparation of this report.
Summary
Infantile myofibromatosis is a rare disorder characterized by the growth of one or more noncancerous (benign) tumors affecting the skin, bone, muscle, soft tissue and rarely the internal organs (viscera). The severity and specific symptoms, including the specific location and number of tumors can vary greatly from one person to another. These tumors do not spread (metastasize) but can grow large enough to cause symptoms by compressing or damaging nearby organs or other parts of the body. Most cases have onset in infants or young children, but adult-onset cases have also been described in the medical literature. Most cases of infantile myofibromatosis occur randomly, for no apparent reason. Rare familial cases (in which more than one family member is affected) have been identified and changes (variants) in two different genes (PDGFRB and NOTCH3) have been found to cause the condition in most of these patients. Treatment depends upon the location of the lesion(s). Spontaneous regression has been reported to occur in many cases; however, recurrence of the lesions has also been reported. Surgery is the main treatment option for focal tumors. PDGFRB variant receptors due to gain of function alleles are often sensitive to the tyrosine kinase inhibitor imatinib.
Introduction
Infantile myofibromatosis was first described as a distinct entity in the medical literature in 1954 by Dr. A.P. Stout. The disorder was initially referred to as congenital generalized fibromatosis. Additional cases were reported in the medical literature under a variety of names including multiple congenital fibromatosis, multiple hamartomas, multiple vascular leiomyomatosis of the newborn and multiple congenital fibromatosis. In 1981, Drs. Chung and Enzinger provided a detailed review of the disorder and introduced the name infantile myofibromatosis.
More than 90% of cases of juvenile myofibromatosis have onset in infancy, although the disorder can first present later in childhood or less often in adults. The tumors can continue to develop throughout an individual’s life.
The specific symptoms of infantile myofibromatosis are broad and the severity can vary. Some infants have mild disease that resolves on its own without treatment (spontaneous regression). Other children develop extensive disease that involves internal organs and can cause life-threatening complications if left untreated. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below and that every individual case is unique. Parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.
The tumors or lesions that characterize infantile myofibromatosis are usually seen as firm, flesh or purple covered bumps (nodules) on the skin or just underneath the top layer of the skin (subcutaneous layer). These superficial lesions may be freely movable; deeper lesions are generally immobile. Skin lesions may be crusted or hardened (indurated). The lesions are usually not painful or tender. The overlying skin may be discolored red or purple and ulcerated. Lesions are also commonly found in muscle, soft tissue and bone and very rarely the internal organs.
Although the tumors that characterize infantile myofibromatosis do not spread (metastasize), they can grow large enough to damage or compress nearby structures in the body. Pain, which occurs when tumors press against adjacent nerves, can develop. In some people. Tumor growth can also cause bone destruction, disfigurement and even physical limitations.
Infantile myofibromatosis is sometimes broken down into separate types, specifically solitary, multicentric and multicentric with visceral involvement.
The solitary form is most common, accounting for approximately 75% of cases. This form occurs predominantly in males and is characterized by one nodule or lesion that most commonly occurs in the skin, often extending into subcutaneous tissue and/or muscle tissue. The nodule is usually found in the head, neck or trunk areas. A solitary nodule of the bone can also occur but is extremely rare.
The multicentric forms are more common in females. The multicentric form without visceral involvement is characterized by multiple nodules that can arise in different areas of the skin, subcutaneous tissue or muscle. The multicentric form with visceral involvement is the most severe form of the disorder and is characterized by multiple growths of the skin, muscles and bones along with the involvement of the internal organs such as the lungs, heart and gastrointestinal tract. In some people, only one organ may be involved; in other people, visceral involvement is widespread. This form of infantile myofibromatosis can cause severe, life-threatening complications depending upon the exact location of the lesion and the specific organs involved.
Most cases of infantile myofibromatosis are thought to occur spontaneously and without a known family history of the disorder. In these patients, the underlying cause of the disorder is unknown. Rare cases of myofibromatosis have been identified that run in families, and variants in two genes have been identified as causing the disorder in some people. These genes are the platelet-derived growth factor receptor beta (PDGFRB) gene and the neurogenic locus notch homolog protein 3 (NOTCH3) gene.
Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect the body.
Infantile myofibromatosis caused by variants in the platelet-derived growth factor receptor beta (PGDFRB) gene can be passed from one generation to the next following autosomal dominant mode of inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Autosomal dominant forms of infantile myofibromatosis may manifest slightly differently in different members of the family who carry the same gene variant. Not all family members will have myofibromas in exactly the same place or at exactly the same age.
Variants in the NOTCH3 gene have been described in rare families with myofibromatosis and in these patients the inheritance is thought to be autosomal recessive. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Infantile myofibromatosis affects males and females in equal numbers. Some reports have noted that males are affected more often by the solitary form and females are affected more often by multicentric forms. The exact incidence is unknown but is estimated to be between 1 in 150,000 to 400,000 live births, reported in different ethnic and geographical groups. Because cases of this rare condition can go undiagnosed or misdiagnosed, determining the true frequency in the general population is difficult.
Although rare, infantile myofibromatosis is the most common fibrous tissue tumor in infancy and early childhood.
A diagnosis of infantile myofibromatosis is based on the microscopic examination of the tissue in a patient with characteristic symptoms and physical examination. Imaging studies including ultrasound and MRI are most often used to visualize the extent of the growths. Imaging techniques may be used to assess the extent of the growths, the progression of the growths and to diagnose recurrence of a growth. Imaging may be used to help evaluate the size, placement and extension of lesions and to aid surgical procedures.
A definitive diagnosis of infantile myofibromatosis requires removal and microscopic (pathological) examination of the affected tissue. Detecting the unique characteristics of the affected tissue distinguishes infantile myofibromatosis from other growths or masses that appear similar clinically and on imaging studies.
Molecular genetic testing (DNA testing) from a blood sample can confirm a genetic cause for infantile myofibromatosis in some patients by detecting variants in specific genes known to cause the disorder such as PDGFRB and NOTCH3. Establishing a genetic diagnosis helps the genetic counselling process by allowing testing of other family members and informing the recurrence risk for future pregnancies. The genetic diagnosis also clarifies prognosis and informs treatment choices.
Genetic counseling is recommended for families. Psychosocial support for the entire family is essential as well.
Treatment
The treatment of infantile myofibromatosis is directed toward the specific symptoms in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, dermatologists and other healthcare professionals may need to work together to plan a child’s treatment.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been conducted on a large group of patients.
Experiences with various treatments have been reported in the medical literature in single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and efficacy of specific medications and treatments for individuals with infantile myofibromatosis.
Specific therapeutic procedures and interventions may vary, depending on the size, number and location(s) of the lesion(s) and symptoms. Decisions concerning the use of drug regimens, surgical treatments and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based on the specifics of their case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preferences and other appropriate factors.
In many patients, infantile myofibromatosis lesions go away on their own without treatment (spontaneous remission). The initial treatment option for many individuals is watchful waiting and observation with appropriate patient education. Watchful waiting or “wait and watch” refers to when physicians follow certain patients with infantile myofibromatosis (i.e. those without visceral involvement or problematic symptoms) without giving treatment until progression of the disease occurs. This allows some people to avoid undergoing surgery or other treatment options for many years or all together in cases with eventual spontaneous remission.
The main treatment option for individuals with infantile myofibromatosis is surgery, which is performed to prevent complications or improve prognosis. Surgical removal of lesions is reserved for cases where there is involvement of internal organs (viscera), symptomatic lesions, or lesions that present an immediate threat due to their location near vital organs and/or if they have shown progression. In approximately 10% of cases, lesions may recur after surgery.
The tyrosine kinase inhibitor imatinib has been successfully used as a targeted therapy for severe myofibromatosis in several patients with PDGFRB gene variants.
Chemotherapy may be used to treat cases where there is involvement of the internal organs and surgery was unsuccessful (i.e. lesions recur) or where surgery is not possible (unresectable) due to the location of the lesions (e.g. too close to a vital organ). Affected children have been successfully treated with a combination of methotrexate and vinblastine. In other patients, interferon alfa or a combination of vincristine, actinomycin D and cyclophosphamide have also been used successfully, but may be reserved for individuals with rapid progression of symptoms.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Goldblum JR, Folpe AL, Weiss SW. Fibrous Tumors in Infancy and Childhood. In: Enzinger’s and Weiss’s Soft Tissue Tumors, 6th ed. Elsevier Saunders, Philadelphia, PA; 2014:256-287.
Chen H, ed. Infantile Myofibromatosis. In: Atlas of Genetic Diagnosis and Counseling, 2nd ed. Humana Press, Totowa, NJ; 2006:545-548.
JOURNAL ARTICLES
Zhao G, Zhu M, Qin C, Liu X, Zhao X. Infantile myofibromatosis: 32 patients and review of literature. J Pediatr Hematol Oncol. 2020;42(8):495-498. doi:10.1097/MPH.0000000000001603
Murray N, Hanna B, Graf N, et al. The spectrum of infantile myofibromatosis includes both non-penetrance and adult recurrence. Eur J Med Genet. 2017;60(7):353-358. doi:10.1016/j.ejmg.2017.02.005
Wu SY, McCavit TL, Cederberg K, Galindo RL, Leavey PJ. Chemotherapy for generalized infantile myofibromatosis with visceral involvement. J Pediatr Hematol Oncol. 2015;37(5):402-405. doi:10.1097/MPH.0000000000000132
Linhares ND, Freire MC, Cardenas RG, et al. Modulation of expressivity in PDGFRB-related infantile myofibromatosis: a role for PTPRG?. Genet Mol Res. 2014;13(3):6287-6292. Published 2014 Aug 15. doi:10.4238/2014.August.15.11
Mashiah J, Hadj-Rabia S, Dompmartin A, et al. Infantile myofibromatosis: a series of 28 cases. J Am Acad Dermatol. 2014;71(2):264-270. doi:10.1016/j.jaad.2014.03.035
Cheung YH, Gayden T, Campeau PM, et al. A recurrent PDGFRB mutation causes familial infantile myofibromatosis. Am J Hum Genet. 2013;92(6):996-1000. doi:10.1016/j.ajhg.2013.04.026
Lee JW. Mutations in PDGFRB and NOTCH3 are the first genetic causes identified for autosomal dominant infantile myofibromatosis. Clin Genet. 2013;84(4):340-341. doi:10.1111/cge.12238
Martignetti JA, Tian L, Li D, et al. Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am J Hum Genet. 2013;92(6):1001-1007. doi:10.1016/j.ajhg.2013.04.024
Levine E, Fréneaux P, Schleiermacher G, et al. Risk-adapted therapy for infantile myofibromatosis in children. Pediatr Blood Cancer. 2012;59(1):115-120. doi:10.1002/pbc.23387
Hausbrandt PA, Leithner A, Beham A, Bodo K, Raith J, Windhager R. A rare case of infantile myofibromatosis and review of literature. J Pediatr Orthop B. 2010;19(1):122-126. doi:10.1097/BPB.0b013e32832e4756
Auriti C, Kieran MW, Deb G, Devito R, Pasquini L, Danhaive O. Remission of infantile generalized myofibromatosis after interferon alpha therapy. J Pediatr Hematol Oncol. 2008;30(2):179-181. doi:10.1097/MPH.0b013e31815e62bb
Arcangeli F, Calista D. Congenital myofibromatosis in two siblings. Eur J Dermatol. 2006;16(2):181-183.
INTERNET
Infantile myofibromatosis. Online Mendelian Inheritance in Man (OMIM). Entry No:228550; Last Update 12/17/2020. Available at: http://omim.org/entry/228550 Accessed May 7, 2024.
Infantile Myofibromatosis. Orphanet. June 2019. Available at: Orphanet: Infantile myofibromatosis Accessed May 7, 2024.
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