reports of constitutional ring chromosome 22 , r(22 ) are rare . the majority of cases with r(22 )
are formed de novo , but there are a few reports of familial transmission1 ) .
a breakpoint resulting in the loss of the short arm and satellite material has few clinical consequences , whereas a breakpoint on the long arm , which can vary in size , can affect phenotypic expression depending on the size of the deletion2 ) .
the phenotypes of individuals with r(22 ) can further be affected by the continuously evolving mosaicism , caused by the mitotic instability of the ring chromosome .
sister chromatid exchanges during mitosis can lead to the formation of dicentric or interlocked rings and subsequent aneuploidy or rearrangements within the chromosome4,5 ) .
central nervous system ( cns ) atypical teratoid / rhabdoid tumors ( atrt ) are rare , highly malignant tumors primarily occurring in young children under 3 years of age .
the majority of atrt cases display genetic alterations of smarcb1 ( ini1/hsnf5 ) , a tumor suppressor gene located on 22q11.2 , resulting in loss of ini1 protein .
ini1 protein is ubiquitously expressed in the nuclei of all normal cells and can be identified using immunohistochemistry .
subsequent loss of ini1 protein expression comprises a relatively specific and sensitive diagnostic marker for atrt6 ) .
here we present a 4 month - old - boy with 46,xy , r(22)(p13q13.3 ) .
high - resolution microarray analysis revealed a 3.5-mb deletion at 22q13.31q13.33 . at 11 months of age , an atrt in the cerebellar vermis
was detected after brain magnetic resonance imaging ( mri ) . to our knowledge , this is the first reported case of a patient with an atrt and r(22 ) in korea .
a 4-month - old boy was referred to department of pediatrics , daegu catholic university of medicine center because of delayed development .
he was the first child of healthy , unrelated korean parents without any known disorders in their family histories .
the mother was 22 years old and the father was 27 years old at the patient 's birth .
the patient was born at 37 weeks of gestational age by uncomplicated spontaneous vaginal delivery , and he weighed 2,500 g. the physical examination revealed unremarkable findings , except generalized hypotonia with decreased deep tendon reflexes of both knee joint was found .
the patient weighed 7.4 kg ( 50th percentile ) , and was 65 cm tall ( 50th percentile ) .
cytogenetic analysis on peripheral blood lymphocytes revealed an r(22 ) in all analyzed cells , specifically 46,xy , r(22)(p13q13.3 ) ( fig .
1 ) . to specify the breakpoint , high - resolution microarray analysis was performed . upon analyses of the genomic dna using an affymetrix cytoscan 750k array analysis ( santa clara , ca
however , the smarcb1 ( ini1/hsnf5 ) gene at 22q11.2 , which lies proximal to the break point , was not deleted .
thus , this chromosomal alteration of the proband was possibly de novo . at 11 months of age ,
the patient was brought to the emergency department with altered consciousness after falling out of his bed at home .
however , it 's unfortunate that we obtained small biopsy specimens . on histopathologic examination ,
the tumor cells , which had some cytoplasm and vesicular nuclei , were larger than cells of medulloblastoma .
the typical rhabdoid tumor cells with eosinophilic cytoplasm were not appeared , and there were no organoid arrangements such as rosette or palisading pattern in the obtained tumor tissue .
immunohistochemical staining for expression of the ini1 protein , showed loss of nuclear expression in the tumor cells ( fig .
, the patient 's condition deteriorated with status epilepticus . a ventriculoperitoneal shunt for hydrocephalus underwent in the referred hospital . the chemotherapy ( vincristine , cisplatin , doxorubicin , and cyclophosphamide ) has been done until now .
ring chromosomes are usually resulted from two terminal breaks in both chromosome arms , followed by fusion of the broken ends , or from the union of one broken chromosome end with the opposite telomere region , leading to the loss of genetic material .
they can also be formed by fusion of subtelomeric sequences or telomere - telomere fusion with no deletion4 ) . in a ring chromosome , the primary deletion associated with ring formation may be accompanied by a secondary loss or gain of material , and the instability in the ring chromosome contributes to the variable phenotypes observed4 ) .
although the phenotypic spectrum of r(22 ) is broad and can range from mild to severe2,7,8 ) , carriers of r(22 ) present with most features of 22q13.3 deletion syndrome2,3 ) . in both r(22 ) and 22q13.3 deletion syndrome , shank3 is suggested to be the most likely candidate gene influencing neurobehavioral features3 ) .
shank3 codes for a scaffolding protein that lies at the core of the postsynaptic density in glutamatergic synapses .
the 22q13.3 deletion syndrome ( or phelan - mcdermid syndrome ) typically results from the loss of the distal long arm of chromosome 22 .
this may result from simple deletions , an unbalanced translocation , or other structural rearrangements involving chromosome 229 ) .
major clinical features include neonatal hypotonia , moderate to severe intellectual impairment , severe delayed or absent expressive language , normal to accelerated growth , autism - associated characteristics , and minor dysmorphic features9 ) .
generally speaking , individuals with the 22q13.3 deletion syndrome have no life threatening organic malformations .
carriers of r(22 ) may also present with the features of nurofibromatosis type 2-associated tumors such as vestibular schwannomas , multiple meningiomas , and neurofibromas . in these cases ,
the pathogenesis of these tumors was explained by the loss of both alleles of the nf2 gene ( neurofibromin 2 ) , a tumor suppressor gene located on chromosome 22q12.210,11 ) .
although the nf2 gene was usually intact within the ring , the ring itself was prone to loss during somatic mitosis , and a pathogenic mutation at the nf2 gene on the remaining chromosome was thought to result in tumor development10,11 ) .
smarcb1 ( ini1/hsnf5 ) is a tumor suppressor gene located on 22q11.2 , proximal to the nf2 gene . in the majority of at / rt cases ,
genetic alterations affecting the smarcb1 ( ini1/hsnf5 ) include homozygous deletions , heterozygous deletions as well as copy - number neutral loss of heterozygosity and mutations affecting each of all nine exons of smarcb16 ) .
immunohistochemistry using an antibody directed against smarcb1 has evolved as a convenient first line diagnostic tool for the diagnosis of atrt .
this is especially relevant in small biopsy specimens , where rhabdoid tumor cells can be missed6 ) . in the past
, cns atrts were often misclassified as a medulloblastoma , primitive neuroectodermal tumors , or a different malignant brain tumor , because of their clinical , histological , and radiographic similarities6,12,13 ) .
however , they are separated from other embryonal tumors by the presence of rhabdoid cells and specific immunohistochemistry6,13 ) .
the coexistence of a cns atrt in a child with an r(22 ) is rare .
a previous case reported a cns atrt in a 4-year - old girl with r(22)14 ) .
in addition , a 2-year - old girl with 22q13.3 deletion syndrome and a cns atrt was reported15 ) . in this case , although the array comparative genomic hybridization analysis of the patient 's blood revealed only a de novo subtelomeric 7.2-mb deletion of chromosome 22q13.2-q13.33 , the results from the frozen tumor tissue demonstrated an acquired somatic frameshift mutation of the ini1 gene and the loss of the de novo germline 22q13 deleted chromosome15 ) .
the net effect was the homogeneous inactivation of the ini1 gene , leading to the development of the atrt15 ) .
although we could not perform a genetic analysis of the tumor in our patient , we think that the atrt may have resulted from the combined loss of the r(22 ) and a pathogenic ini1 mutation on the remaining chromosome 22 .
therefore , monitoring for not only neurofibromatosis type 2-associated tumors , but also for atrts should be performed in all carriers with an r(22 ) .
the familial transmission of r(22 ) from a normal woman to her clinically affected daughter was also reported .
the benign r(22 ) in a parent may undergo further rearrangements not only during mitosis , but also during meiosis to produce an unbalanced chromosome associated with developmental abnormalities2 ) .
therefore , both the gene deletion associated with ring formation , and the secondary genetic imbalance , should be considered .
 reports of constitutional ring chromosome 22 , r(22 ) are rare . 
 individuals with r(22 ) present similar features as those with the 22q13 deletion syndrome . 
 the instability in the ring chromosome contributes to the development of variable phenotypes . 
 central nervous system ( cns ) atypical teratoid rhabdoid tumors ( atrts ) are rare , highly malignant tumors , primarily occurring in young children below 3 years of age . 
 the majority of atrt cases display genetic alterations of smarcb1 ( ini1/hsnf5 ) , a tumor suppressor gene located on 22q11.2 . 
 the coexistence of a cns atrt in a child with a r(22 ) is rare . 
 we present a case of a 4-month - old boy with 46,xy , r(22)(p13q13.3 ) , generalized hypotonia and delayed development . 
 high - resolution microarray analysis revealed a 3.5-mb deletion at 22q13.31q13.33 . at 11 months , the patient had an atrt ( 5.6 cm5.0 cm7.6 cm ) in the cerebellar vermis , which was detected in the brain via magnetic resonance imaging . 
Introduction
Case report
Discussion