Infantile Myofibromatosis and Idiopathic Basal Ganglia Calcification via the PDGFRB Gene

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, uterine and adult onsets have 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).

Familial Idiopathic Basal Ganglia Calcification (IBGC), also known as Fahr’s syndrome, is a neurological disorder characterized by abnormal deposits of calcium in areas of the brain that control movement. The radiological characteristics of IBGC consist of bilateral and symmetrical calcification of the basal ganglia. Additional areas of the brain may also be affected. IBGC is clinically heterogeneous. Symptoms usually begin during the fourth and fifth decade of life. Childhood and adolescent onset have been also reported. Movement disorders in the form of dystonia, tremor and chorea are the initial and most common clinical manifestations of IBGC. As the disease progress neurological and neuropsychiatric abnormalities are detected and include seizures, spasticity, headache, dysarthria, psychosis, mood disturbances, cognitive decline, and dementia (Manyam 2005; Nicolas et al. 2013b).

Abnormal deposit of calcium in the brain is a common finding usually associated with aging. However, familial IBGC is rare, with less than 1/1,000,000 people affected worldwide (Ellie et al. 1989).

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 recently implicated in the disease. Two germline missense mutations 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).

Familial IBGC is a genetically heterogeneous autosomal dominant disorder. Simplex cases with no apparent family history have been also reported. To date, three genes have been associated with the disease: SLC20A2, PDGFB, and PDGFRB. Three pathogenic missense variants in PDGFRB have been recently reported both in familial and apparently simplex cases (Nicolas 2013a; 2013b).

PDGFRB encodes the platelet-derived growth factor receptor beta, a tyrosine kinase receptor that has been 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).

Pathogenic variants in the PDGFRB gene are the major cause of familial IM; they were found in 12 out of 13 IM-affected families (Cheng et al. 2013; Martignetti et al. 2013). This test will detect PDGFRB pathogenic variants in ~ 4% of patients with IBGC (Nicolas et al. 2013b).

This test provides full coverage of all coding exons of the PDGFRB gene 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 full 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).