2q36.1

CDHS,HUP2,WS1,WS3

Alveolar Rhabdomyosarcoma (ARMS)

ARMS is one subtype of a family of pediatric soft tissue tumors that is related to the skeletal muscle lineage. In contrast to the embryonal rhabdomyosarcoma (ERMS), the other major subtype in this family, ARMS often occurs in adolescents and young adults, with primary tumors located in the vicinity of skeletal muscle, such as in the extremities and trunk.

In contrast to the favorable outcome in most cases of ERMS, ARMS is associated with an unfavorable prognosis. In the IRS-IV clinical trial, the three year failure-free survival rate was 66% for patients presenting without metastatic disease and 16% for patients presenting with metastatic disease (compared to 83% and 37% for non-metastatic and metastatic ERMS, respectively). This unfavorable prognosis in ARMS is related to the propensity for early and wide dissemination, often involving bone marrow, and to poor response to chemotherapy.

Chromosomal studies identified nonrandom chromosomal translocations that distinguish the majority of ARMS tumors from ERMS and other pediatric solid tumors. The t(2;13)(q35;q14) translocation is the most prevalent and the t(1;13)(p36;q14) is identified in a smaller subset of cases.

The 2;13 or 1;13 chromosome translocation juxtapose the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1 with the FKHR (FOXO1A) gene on chromosome 13 to generate two chimeric genes. These chimeric genes are transcribed to generate chimeric transcripts, of which the PAX3-FKHR and PAX7-FKHR transcripts are the most highly and consistently expressed of the pair of potential products. Based on RT-PCR assays for these chimeric transcripts, approximately 60% of ARMS cases express PAX3-FKHR and thus contain the t(2;13), 20% express PAX7-FKHR and thus contain the t(1;13), and 20% are fusion-negative.

The PAX3-FKHR and PAX7-FKHR chimeric genes encode fusion proteins that contain the intact DNA binding domain of PAX3 or PAX7 in the N-terminal region fused in frame with a C-terminal FKHR (FOXO1A) segment containing the transactivation domain. The chromosomal changes in ARMS result in high level expression, potent transcriptional activity, and constitutive nuclear localization of the PAX3-FKHR or PAX7-FKHR fusion products. The end result is exaggerated activity at multiple biological levels that converges to inappropriate activation of PAX3/PAX7 target genes and ultimately contributes to tumourigenic behavior.

Waardenburg syndrome (type I et III)

Waardenburg syndrome (WS) is an inherited autosomal-dominant disorder characterized by sensorineural hearing loss (of varying severity), dystopia canthorum (lateral displacement of inner corners of eye), and pigmentary disturbances of the eye, skin and hair. It is a common cause of inherited deafness in infants. Depending on additional symptoms, WS is classified into four types, WS1, WS2, WS3, and WS4, with only WS1 and WS3 being associated with PAX3 mutations. Deletions, insertion, base pair substitution, or dominant point mutations of PAX3 cause WS1 and WS3. WS3 (Klein-Waardenburg syndrome) is similar to WS1 but WS3 is also characterized by musculoskeletal abnormalities, usually involving the upper limbs. It should be noted that WS3 is often associated with deletions of the long arm of chromosome 2 involving multiples genes including PAX3 whereas WS1 is generally is associated with mutations within the PAX3 gene. WS2 is heterogenous, being caused by mutations in the MITF gene in some but not all affected families. WS4 is caused by mutations in the EDN3, EDNRB, or SOX10 ID genes.

Craniofacial-deafness-hand syndrome (CDHS)

Craniofacial-deafness-hand syndrome is inherited as an autosomal dominant mutation. CDHS shows clinical characteristics of the absence or hypoplasia of the nasal bones, profound sensorineural deafness, a small and short nose with slitlike nares, hypertelorism, short palpebral fissures, and limited movement at the wrist and ulnar deviations of the fingers. A missense mutation (Asn47Lys) in the paired domain (exon 2) of PAX3 was detected in a family of three (a mother and two children) first reported with this syndrome.