PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma in Schuurs-Hoeijmakers syndrome.

PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma (ARMS) developed in a patient presenting with intellectual disability and dysmorphic facial features. Whole exome sequencing analysis of a germline sample identified a PACS1 c.607 C>T de novo variant and the patient was diagnosed with Schuurs-Hoeijmakers syndrome (SHS). SHS is a rare disease characterized by intellectual disability and dysmorphic facial features, among various physical abnormalities, due to PACS1 c.607 C>T de novo variant. Due to the rarity of the SHS, diagnosis based on phenotypic information is difficult. To date, there have been no previous reports describing malignancy associated with SHS. Comprehensive somatic mutation analysis revealed a unique pattern of genetic alterations in the PAX3/7-FOXO1 fusion-negative ARMS tumor, including mutations in the oncogene, HRAS; MYOD1, a molecule essential for muscle differentiation; and KMT2C and TET1, genes encoding factors involved in epigenetic regulation. Although the role of PACS1 in tumorigenesis is unclear, it is reported to function in apoptosis regulation. Our case suggests that PACS1 could have a novel role in oncogenesis.

An Adult Patient With Rare Primary Intracranial Alveolar Rhabdomyosarcoma.

We report a rare case of primary intracranial alveolar rhabdomyosarcoma (ARMS) in the right temporal lobe of a 51-year-old male. ARMS is one of 3 histological subtypes of rhabdomyosarcoma that most commonly presents in older children and younger adults. To our knowledge, there have been no prior published reports of primary intracranial ARMS in adults. Known cases of intracranial ARMS in adults are due to central nervous system (CNS) metastases from the head and neck and extremities. Diagnostic workup did not reveal any primary source outside the CNS. Given that risk factors for ARMS have not been studied in adults, it is difficult to ascertain what aspects of this patient's clinical history may have contributed to his diagnosis. Interestingly, he had prior history of traumatic brain injury requiring evacuation of a right fronto-temporal intraparenchymal hematoma.

IRIZIO: a novel gene cooperating with PAX3-FOXO1 in alveolar rhabdomyosarcoma (ARMS).

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children with an annual incidence of five new cases per million. Alveolar rhabdomyosarcoma (ARMS) is characterized by the t(2;13) or t(1;13) chromosomal translocations, which generate the PAX3-FOXO1 or PAX7-FOXO1 fusion genes, respectively. The oncogenic activity of PAX3-FOXO1 has been demonstrated in vitro and in vivo, yet expression of the fusion protein alone in primary myoblasts or a mouse model is insufficient for tumorigenic transformation. To identify genes cooperating with PAX3-FOXO1 in ARMS tumorigenesis, we generated a retroviral complementary DNA (cDNA) expression library from the Rh30 ARMS cell line. Arf-/- myoblasts expressing PAX3-FOXO1 and the retroviral cDNA library rapidly formed tumors after subcutaneous injection into NOD-SCID mice. Tumors formed by Arf-/-/PAX3-FOXO1/MarX-library myoblasts contained an unknown cDNA, encoding the C-terminus of the Homo sapiens hypothetical protein, FLJ10404, herein named IRIZIO. Expression of full length IRIZIO cDNA also cooperated with PAX3-FOXO1 in the transformation of Arf-/- myoblasts. Given that IRIZIO is expressed at increased levels in RMS, it might contribute to rhabdomyosarcomagenesis in humans.

PDGFR-A is a therapeutic target in alveolar rhabdomyosarcoma.

Alveolar rhabdomyosarcoma is an aggressive skeletal muscle cancer of childhood. Our initial studies of rhabdomyosarcoma gene expression for patients enrolled in a national clinical trial suggested that platelet-derived growth factor receptor A (PDGFR-A) may be a mediator of disease progression and metastasis. Using our conditional mouse tumor models that authentically recapitulate the primary mutations and metastatic progression of alveolar rhabdomyosarcomas in humans, we found by immunoblotting and immunokinase assays that PDGFR-A and its downstream effectors, mitogen-activated protein kinase and Akt, were highly activated in both primary and metastatic tumors. Inhibition of PDGFR-A by RNA interference, small molecule inhibitor or neutralizing antibody had a dramatic effect on tumor cell growth both in vitro and in vivo, although resistance evolved in one-third of tumors. These results establish proof-of-principal for PDGFR-A as a therapeutic target in alveolar rhabdomyosarcoma.

Transgenic mice expressing PAX3-FKHR have multiple defects in muscle development, including ectopic skeletal myogenesis in the developing neural tube.

The t(2;13) chromosomal translocation is found in the majority of human alveolar rhabdomyosarcomas (RMS). The resulting PAX3-FKHR fusion protein contains PAX3 DNA-binding domains fused to the potent transactivation domain of FKHR, suggesting that PAX3-FKHR functions to deregulate PAX3-specific target genes and signaling pathways. We previously developed transgenic mice expressing PAX3-FKHR under the control of mouse Pax3 regulatory sequences to test this hypothesis. We reported that PAX3-FKHR interferes with normal Pax3 developmental functions, with mice exhibiting neural tube and neural crest abnormalities that mimic those found in Pax3-deficient Splotch mice. Here we expanded those studies to show that developmental expression of PAX3-FKHR results in aberrant myogenesis in the developing somites and neural tube, leading to ectopic skeletal muscle formation in the mature spinal cord. Gene expression profiling indicated that PAX3-FKHR expression in the developing neural tube induces a myogenic pattern of gene expression at the expense of the normal neurogenic program. Somite defects in PAX3-FKHR transgenic animals resulted in skeletal malformations that included rib fusions and mis-attachments. As opposed to the neural tube defects, the severity of the rib phenotype was rescued by reducing Pax3 levels through mating with Splotch mice. Embryos from the transgenic line expressing the highest levels of PAX3-FKHR had severe neural tube defects, including exencephaly, and almost half of the embryos died between gestational ages E13.5-E15.5. Nearly all of the embryos that survived to term died after birth due to severe spina bifida, rather than the absence of a muscular diaphragm. These studies reveal a prominent role for PAX3-FKHR in disrupting Pax3 functions and in deregulating skeletal muscle development, suggesting that this fusion protein plays a critical role in the pathogenesis of alveolar RMS by influencing the commitment and differentiation of the myogenic cell lineage.

Alveolar rhabdomyosarcoma in infantile spinal muscular atrophy: coincidence or predisposition?

We report two unrelated patients with infantile spinal muscular atrophy (SMA) types II and IIIa who developed alveolar rhabdomyosarcoma (ARMS) at 15 and 19 years, respectively. The tumours were located in the forearm, within severely atrophic flexor muscles. They displayed a similar histology and shared the most common translocation, t(2;13)(q35;14) in ARMS. Since cell proliferation is increased in de- and regenerating muscle and the PAX3/FKHR fusion protein activates myogenic transcription, it is tempting to speculate whether severe muscle atrophy in SMA might predispose to malignant transformation in long-standing disease.

[Alveolar rhabdomyosarcoma with massive infiltration of the bone marrow as its initial manifestation]. / Rabdomiosarcoma alveolar con infiltración masiva de medula ósea como manifestación inicial.

We report a case of alveolar rhabdomyosarcoma (AR) with massive infiltration of bone marrow at presentation, and initial diagnosis in bone marrow aspirate. A 35 year old man presented with a submandibular mass, and hematomas after mild traumatisms. Peripheral blood showed thrombocytopenia and a normocytic anaemia. Bone marrow film showed diffuse involvement by undifferentiated blasts with rhabdomyoblastic features. Subsequent biopsy of submandibular lymph node confirmed the diagnosis with positivity for specific muscle actin and desmin, and negativity for lymphoid markers. Initial presentation of AR with extensive bone marrow involvement is extremely rare, and it could lead to wrong diagnosis and treatment of acute leukaemia, with the serious consequences that this would have. Immunohistochemical study and morphologic differential features can be of great diagnostic help.