Infantile Myofibromatosis Panel

Infantile myofibromatosis (IM), previously known as congenital generalized fibromatosis, is characterized by the development of tumors in various tissues and organs. IM affects mostly infants and young children. Although tumors are usually detected at birth or during the first two years of life, adult onset has been also reported (Chung and Enzinger 1981).

Two main types of IM, solitary and multicentric, are distinguished. Each type is further divided in two groups based on the presence or absence of visceral involvement (Wiswell et al. 1988).

The solitary type is characterized by the development of a single nodule mainly in the bones, striated muscle, skin, or subcutaneous tissues. In rare cases, solitary tumors have been reported in the viscera.

The multicentric type is characterized by the development of multiple nodules in various organs. Visceral involvement is common in this type. The lungs, heart, gastrointestinal tract, pancreas, liver, and bones are most commonly affected. Involvement of the central nervous system appears to be rare (Wada et al. 1998). IM with visceral involvement has a poor prognosis, although spontaneous regression has been reported in some cases (Teng et al. 1963).

About half the patients with IM have the solitary type and the other half have the multicentric type. The solitary type affects older individuals in about 20% of patients. Both solitary and multicentric IM have a good prognosis in the absence of visceral involvement when the tumors regress spontaneously during the first years of life. However, new tumors may develop later.

IM is clinically heterogeneous. Symptoms are highly variable and depend on the number and location of tumors. The disease may be limited to the skin in some patients, while several visceral organs are involved in other patients. Affected related members may present either with the solitary type with no visceral involvement or the multicentric visceral type (Cheung et al. 2013). The tumors consist of soft tissues abnormalities, and are usually benign. However, complications may occur when the tumors affect the normal function of vital organs such as the brain or viscera.

Although rare, IM has been reported in various ethnic and geographical groups (Cheung et al. 2013).

In most of the IM-affected families reported, the disease is inherited in an autosomal dominant manner. In rare families, a recessive mode of transmission is speculated. It has been argued that family history may be difficult to obtain due to the spontaneous regression of tumors (Narchi 2001).

Autosomal Dominant IM is genetically heterogeneous. Two genes, PDGFRB and NOTCH3, have been implicated in the disease.

Two germline pathogenic missense variants in the PDGFRB gene, c.1681C>T (p.Arg561Cys) and c.1978C>A (p.Pro660Thr) have been reported. The c.1681C>T variant was reported in families from different ethnic and geographical populations (Cheng et al. 2013; Martignetti et al. 2013; Arts et al. 2016).

To date, only one heterozygous germline missense variant in NOTCH3, 4556T>C (p.Leu1519Pro), has been implicated in IM. This variant was identified via whole exome sequencing. Evidence for pathogenicity include co-segregation of the variant in a large family with a history of IM and no pathogenic variants in PDGFRB; absence from large population databases of genetic variations; and localization in the hetero-dimerization domain of the protein (Martignetti et al. 2013; Arts et al. 2016).

PDGFRB encodes the platelet-derived growth factor receptor beta, a tyrosine kinase receptor that is involved in several cellular processes including proliferation, differentiation, survival, and migration. It has also been suggested that the PDGFRB/ PDGFB pathway is involved in the calcification of vascular smooth muscle cells (Diliberto et al. 1991).

NOTCH3 encodes a transmembrane protein that is a member of the NOTCH receptor family. NOTCH signaling is involved in the regulation of various processes in both the embryo and the adult (Joutel 2000).

In vitro studies have previously revealed interactions between the Notch and PDGF signaling pathways (Jin et al. 2008).

Pathogenic variants in the PDGFRB gene are the major cause of familial IM; they were found in about 90% of IM-affected families (Cheng et al. 2013; Martignetti et al. 2013). Pathogenic variants in the NOTCH3 gene appear to be a rare cause of IM. Such a variant was identified in one out of 9 IM-affected families (Martignetti et al. 2013).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).