Myofibromatosis, Infantile, 1

A number sign (#) is used with this entry because infantile myofibromatosis-1 (IMF1) is caused by heterozygous mutation in the PDGFRB gene (173410) on chromosome 5q32.

Description

Infantile myofibromatosis is a rare mesenchymal disorder characterized by the onset of nodules in the skin, striated muscles, bones, and, more rarely, visceral organs. Subcutaneous or soft tissue nodules commonly involve the skin of the head, neck, and trunk. Skeletal and muscular lesions occur in about 50% of patients. Lesions may be solitary or multicentric, and they may be present at birth or become apparent in early infancy or occasionally in adult life (summary by Arcangeli and Calista, 2006).

Genetic Heterogeneity of Infantile Myofibromatosis

See also IMF2 (615293), caused by mutation in the NOTCH3 gene (600276).

Clinical Features

Congenital generalized fibromatosis is a rare disorder characterized by multiple fibroblastic tumors involving skin, striated muscles, bones, and viscera. The tumors are present at birth or develop during the first weeks of life. This disorder was described by Stout (1954), who distinguished it from other forms of juvenile fibromatosis. The radiologic findings are similar to those of Ollier disease (166000). Multiple cystic lesions involve the metaphyses. Multiple soft tissue nodules occur (Shnitka et al., 1958), as in multiple neurofibromatosis (162200), but a cutaneous pigmentary anomaly is not a feature.

Familusi et al. (1976) observed gingival hypertrophy and ankylosis of many joints in a Nigerian infant with congenital generalized fibromatosis.

Baer and Radkowski (1973) distinguished congenital multiple fibromatosis which carries a better prognosis because viscera are not affected. According to their tabulation of reported cases, Bartlett et al. (1961) and Kauffman and Stout (1965) reported patients of both categories. Stout (1954) and Teng et al. (1963) dealt with congenital generalized fibromatosis and Heiple et al. (1972) reported on congenital multiple fibromatosis (despite the title of his paper). Some consider the tumors a form of hamartomatosis since they often contain smooth muscle and vascular channels in addition to fibrous tissue.

Chung and Enzinger (1981) preferred the term juvenile myofibromatosis because of the presumed myofibroblastic origin of the cells. The prognosis is poor when several internal organs are affected; 80% of such infants are said to die in the first 4 months of life. On the other hand, complete spontaneous regression has been observed (Teng et al., 1963). These characteristics are reminiscent of those of neuroblastoma (256700).

Venencie et al. (1987) described infant brothers with cutaneous and skeletal myofibromas. The cutaneous lesions healed spontaneously and completely.

Castro et al. (1987) reported a case of multicentric fibromatosis in a 35-year-old woman who had first onset of a cutaneous tumor at age 5 years. Although the parents came from Jewish lineages that had resided in the same city in Morocco for many generations, no consanguinity was known. One aunt and a female cousin had similar subcutaneous tissues, but the sibs, parents, and grandparents were apparently free of tumors.

Bracko et al. (1992) described 2 brothers with multicentric infantile myofibromatosis. In both, tumors were present at birth; the tumors regressed spontaneously but new lesions developed throughout the follow-up periods of 15 and 8 years.

Narchi (2001) described a family strongly supporting autosomal recessive inheritance of infantile myofibromatosis. A healthy woman, married to her first cousin, had 4 children, 3 of whom (2 sons and 1 daughter) were diagnosed with infantile myofibromatosis, confirmed by histopathologic studies. Some lesions recurred and one of the sibs developed intraorbital and intracranial myofibromas that required surgery. After a divorce, the woman married her previous husband's half brother (from the same father) who was also healthy. Their first 2 children were unaffected, but the third child, who was female, also developed myofibromatosis. The parents themselves denied having neonatal lesions that spontaneously regressed.

Ikediobi et al. (2003) reported a 3-generation family with infantile myofibromatosis. The proband presented on the first day of life with multiple cutaneous firm, rubbery, flesh-colored nodules on the scalp, lateral aspect of the left thigh, and left side of the back. Histopathology of 1 lesion showed a deep dermal proliferation of spindle cells, with minimal atypia and rare mitotic figures, consistent with the diagnosis of myofibroma. MRI of the chest and abdomen showed 2 small nodules within the right paraspinal muscle; no skeletal or other visceral lesions were evident. By 6 months of age, her skin nodules involuted to firm, subcutaneous depressions. She had no systemic manifestations. Family history revealed that her father, paternal grandfather, and paternal aunt had similar skin nodules at birth that spontaneously resolved without systemic sequelae. The patient's paternal aunt had 4 affected children. One child had skin myofibromas, skeletal myofibromas, and 1 ocular myofibroma that resulted in enucleation of the affected eye. Another child had myofibromas in the peritoneal cavity resulting in intestinal obstruction, multiple operative procedures, and permanent colostomy. The other 2 children had skin-limited disease.

De Montpreville et al. (2004) reported an unusual case of infantile myofibromatosis in a 12.5-month-old girl who presented with hemiplegia and was found to have an ischemic cerebral lesion. Echocardiography revealed 2 small 1 to 1.5-cm nodules in the left atrium; both were surgically excised. Histologic examination showed spindle-shaped cells arranged in bundles, rare mitotic figures, and fibrosis, consistent with myofibromatosis. The underlying mitral valvular base was only superficially invaded, and de Montpreville et al. (2004) suggested that this child did not have a visceral form of the disorder, but rather that the lesions in the heart represented a subendothelial lesion. The patient had no other obvious skin lesions and no visceral involvement. As a neonate, her father had had congenital fibromatosis of the laryngeal nerve as well as cutaneous nodules, suggesting autosomal dominant inheritance of the disorder.

In a family reported by Zand et al. (2004) in which there were 3 proven instances of male-to-male transmission and 2 other suspected instances, the proband presented at birth with a mass in the superficial soft tissue of the left upper quadrant of the abdominal wall. At 3 weeks of age, an additional mass was noted behind his left knee, while at 6 weeks of age the abdominal wall mass regressed. The family history was notable for a brother and father who had been diagnosed with biopsy-proven infantile myofibromatosis. The proband of the second family reported by Zand et al. (2004) was evaluated at 3 years of age for a persistent 'scalp mass' which had presented during infancy. A mass was also present on the shoulder. By the age of 16 years, she had developed a total of 6 soft tissue lesions without complication. Her father and a paternal first cousin with biopsy-proven infantile myofibromatosis, but had a much more complicated clinical course. The father developed both soft tissue and visceral lesions throughout his life, including lesions in his meninges, kidney, and vocal cords, requiring tracheotomy placement. At 9 months of age the proband's first cousin developed an intususseption. Pathology obtained during surgical repair was consistent with multiple myofibromas, which presumably served as a lead point to the intususseption. The proband of another family reported by Zand et al. (2004) presented at birth with a large pedunculated mass attached to the right parietooccipital scalp. Cranial imaging and pathologic findings confirmed solitary infantile myofibromatosis. Her brother had previously undergone surgery in infancy for a small thigh mass, also found to be a myofibroma.

Cheung et al. (2013) reported 4 unrelated families with autosomal dominant infantile myofibromatosis. One family was of Chinese origin with affected father and 2 children. The father had a solitary myofibroma at an early age that did not require further treatment. The son was diagnosed at age 4 years with multiple myofibromas of the skin, most of which spontaneously regressed. The daughter presented at age 6 months with multiple myofibromas of the skin and visceral myofibroma of the orbit and supranasal region. In a second family, the mother had multiple subcutaneous myofibromas on the head and neck, shoulder, back, and abdominal wall. Her son had onset in the first year of life of multiple lesions on the abdominal wall and left upper gingival border. Affected members of the third family, of French Canadian origin, had had multiple myofibromas of the skin on the face and upper arms that spontaneously regressed at the age of 4 years, similar to their father. The fourth family was of European ancestry and had previously been reported by Smith and Orchard (2011). The 2 affected brothers were diagnosed with multiple myofibromas at ages 3 and 11 weeks, respectively, with no clinical evidence of visceral involvement. The mother had swelling in the left side of her neck at 7 months of age, which was found to be fibromatosis and subsequently excised.

Inheritance

Hower et al. (1971) described affected half sisters with the same mother.

Bartlett et al. (1961) observed 4 cases among first cousins. The mother of affected brother and sister and the father of another affected brother-sister pair were sibs.

Although the report of Venencie et al. (1987) and other reports suggest autosomal recessive inheritance, such cannot explain the affected half sisters reported by Hower et al. (1971) and the cases of this disorder in a female infant and her father reported by Jennings et al. (1984).

Bracko et al. (1992) reviewed families with this disorder in more than one member. The occurrence of the disorder in 8 sets of sibs, with consanguinity in 2, favored autosomal recessive inheritance; as noted previously, however, the occurrence in half sisters and in successive generations favored autosomal dominant inheritance.

Narchi (2001) described a family strongly supporting autosomal recessive inheritance of infantile myofibromatosis. From a review of the literature, Narchi (2001) concluded that autosomal recessive inheritance is most likely.

The transmission pattern of infantile myofibromatosis in the family reported by Ikediobi et al. (2003) was consistent with autosomal dominant inheritance with variable penetrance, since the severity of the disorder differed within the family.

Zand et al. (2004) presented 3 families with infantile myofibromatosis inherited in an autosomal dominant manner. In one family, there were 3 proven instances of male-to-male transmission and 2 other suspected instances. Zand et al. (2004) were prompted to reassess reported pedigrees that had suggested autosomal recessive inheritance. They pointed out that most nodules tend to regress spontaneously, making family history difficult to obtain and/or confirm. They suggested that all infantile familial myofibromatosis may be autosomal dominant or, alternatively, there may be genetic heterogeneity.

Arcangeli and Calista (2006) reported a brother and sister, born to nonconsanguineous parents, with infantile myofibromatosis. Their review of the international literature showed that although most of the reported cases were sporadic, about 15 families, including theirs, had more than one affected family member.

Diagnosis

The diagnosis of infantile myofibromatosis is based on histopathologic grounds. Well-circumscribed nodules, formed by a central hemagiopericytoma-like vascular proliferation, are surrounded by sweeping fascicles of fibroblastic and myofibroblastic cells (summary by Arcangeli and Calista, 2006).

Molecular Genetics

In affected members of 4 unrelated families with infantile myofibromatosis, Cheung et al. (2013) identified the same heterozygous missense mutation in the PDGFRB (R561C; 173410.0003). The families were of Chinese, European, French Canadian, and French origin, respectively. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing in the first 2 families, segregated with the phenotype in all families and was not found in several large control databases. In addition, tumor tissue from 1 of the patients who carried a germline R561C mutation harbored a somatic PDGFRB mutation (N666K; 173410.0004) that was predicted to be damaging. Structural modeling indicated that the R561C mutation was located within the cytoplasmic juxtamembrane (JM) region between the helical transmembrane segment and the kinase domain, and was predicted to compromise the autoinhibitory role of the JM domain, leading to increased kinase firing and promoting the formation of myofibromas in tissues with high PDGFRB signaling activity. Modeling also predicted that the N666K mutation would favor an active kinase formation. In vitro functional studies were not performed. Sequencing of the PDGFRB gene in 5 individuals with nonfamilial IMF did not identify any causative mutations.

Martignetti et al. (2013) identified a heterozygous R561C mutation in the PDGFRB gene in affected members from 7 unrelated families with autosomal dominant infantile myofibromatosis. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control databases. Another family with the disorder carried a different heterozygous mutation in the PDGFRB gene (P660T; 173410.0004). Some of the families had previously been reported (Jennings et al., 1984; Ikediobi et al., 2003; Zand et al., 2004; de Montpreville et al., 2004).

Associations Pending Confirmation

For discussion of a possible association between variation in the NDRG4 gene and infantile myofibromatosis, see 614463.0001.