miller - dieker syndrome ( mds ) is a multiple - malformation syndrome in which the patients show severe lissencephaly with facial dysmorphism at birth . lissencephaly varies in severity from agyria to pachygyria and is linked to defects in the lissencephaly gene ( lis1 ) , which is located in 17p13.3 . in patients with mds , the loss of the lis1 gene can occur by deletion , ring chromosome formation , or transmission of a parental chromosome with an unbalanced translocation , including transmission of chromosome 17p13.3 . in approximately 80% of the cases of mds in infants , the disease is believed to be caused by a de novo deletion , and the remaining cases are caused by inheritance . in the case of a parental balanced translocation , the chromosomes of the offspring usually show an unbalanced translocation combined with partial trisomy of another autosomal segment . various 17p13.3 microdeletions inherited from a parent with a balanced translocation of chromosome 17 and another chromosome have been reported [ 4 , 6 ] . most patients with an unbalanced translocation show a combination of the findings of mds and additional unique phenotypes because of the involvement of segments of various autosomes . in this report , we report the findings for a female infant who had der(17)t(12;17)(q24.33;p13.3)pat showing a nearly pure large deletion ( ~4.6 mb ) involving 17p13pter without evidence of duplication of 12q24.33qter , which was confirmed by high density array comparative genome hybridization ( cgh ) . recently , grosso et al . also reported a case of mds with periventricular nodular heterotopia caused by an unbalanced t(12;17)(q24.31;p13.3 ) translocation . their case had a relatively large duplication ( ~11 mb ) of 12q24.31qter , but our case showed no definite duplication of 12q in the array cgh analysis . our case could have been misdiagnosed as a classic case of mds resulting from the deletion of 17p13.3pter because the smallest segment of 12q24.33qter according to the literatures was involved . if such patients are incorrectly diagnosed with mds caused by de novo 17p13.3 deletion , the resultant improper genetic counseling may make it difficult to exactly predict the potential risk of recurrent lissencephaly for successive pregnancies . the female patient was born to a healthy g4p2 mother and a healthy non - consanguineous father at 35 + 5 weeks of gestation by cesarean delivery because of preterm labor and intrauterine growth retardation . the parents ' first child was diagnosed with lissencephaly after birth and died at 3 months of age . the second baby was aborted following the diagnosis of a brain anomaly by fetal ultrasound . the patient was their third baby and was diagnosed with ventriculomegaly during the antepartum period . the birth weight was 1,680 g ( < 3rd percentile ) , the length of the baby was 42.3 cm ( < 3rd percentile ) , and the head circumference was 30 cm ( 3rd-10th percentile ) . at birth , she was noted to have facial dysmorphism , including prominent frontal bossing , a high nasal bridge , low - set ears , a thin inferior lip , micrognathia , and arthrogryposis . on the 3rd day after birth an electroencephalogram showed diffuse brain dysfunction , and magnetic resonance imaging ( mri ) showed lissencephaly with band heterotopia and agenesis of the corpus callosum ( fig . , she was taken to the emergency room because of generalized tonic seizures and showed failure to thrive . conventional cytogenetic analysis of the proband revealed a possible abnormal karyotype [ 46,xx , del(17)(p13 ) ] ( fig . cytogenetic analysis was also performed on the proband 's parents because the recurrent abnormal phenotypes during the 3 consecutive pregnancies strongly suggested that mds in this case might have resulted from an unbalanced segregation of the parental balanced translocation of 17p with other chromosomes . cytogenetic analysis of the proband 's father showed a shortened p - arm of chromosome 17 ( fig . however , the small translocated telomeric segments of chromosome 17 could not be definitively identified by conventional cytogenetic analysis . in order to identify the position where the terminal segment of chromosome 17p13.3pter was translocated , fish with a miller - dieker / lissencephaly region probe ( vysis , abbott laboratories , abbott park , il , usa ) was performed on the same g - banded metaphase chromosomes according to the manufacturer 's instructions . the mds probe signal ( 17p13.3 ) was detected on chromosome 12qter , indicating an unbalanced segregation of t(12;17 ) ( fig . further characterization of the size and boundaries of the cytogenetic abnormalities of the proband was performed using human genome cgh microarray kit 244 ( agilent technologies , palo alto , ca , usa ) , which consists of approximately 244,000 arrayed 60-base oligonucleotide - probes that span both coding and non - coding sequences with an average spatial resolution of about 15 kb . array cgh showed about a 4.6-mb deletion involving 17p13.3 , but it did not show duplication at 12q [ arr17p13.3p13.2 ( 28,969 - 4,653,156)1 pat ] ( fig . the female patient was born to a healthy g4p2 mother and a healthy non - consanguineous father at 35 + 5 weeks of gestation by cesarean delivery because of preterm labor and intrauterine growth retardation . the parents ' first child was diagnosed with lissencephaly after birth and died at 3 months of age . the second baby was aborted following the diagnosis of a brain anomaly by fetal ultrasound . the patient was their third baby and was diagnosed with ventriculomegaly during the antepartum period . the birth weight was 1,680 g ( < 3rd percentile ) , the length of the baby was 42.3 cm ( < 3rd percentile ) , and the head circumference was 30 cm ( 3rd-10th percentile ) . at birth , she was noted to have facial dysmorphism , including prominent frontal bossing , a high nasal bridge , low - set ears , a thin inferior lip , micrognathia , and arthrogryposis . on the 3rd day after birth an electroencephalogram showed diffuse brain dysfunction , and magnetic resonance imaging ( mri ) showed lissencephaly with band heterotopia and agenesis of the corpus callosum ( fig . , she was taken to the emergency room because of generalized tonic seizures and showed failure to thrive . conventional cytogenetic analysis of the proband revealed a possible abnormal karyotype [ 46,xx , del(17)(p13 ) ] ( fig . 2a ) . cytogenetic analysis was also performed on the proband 's parents because the recurrent abnormal phenotypes during the 3 consecutive pregnancies strongly suggested that mds in this case might have resulted from an unbalanced segregation of the parental balanced translocation of 17p with other chromosomes . cytogenetic analysis of the proband 's father showed a shortened p - arm of chromosome 17 ( fig . however , the small translocated telomeric segments of chromosome 17 could not be definitively identified by conventional cytogenetic analysis . in order to identify the position where the terminal segment of chromosome 17p13.3pter was translocated , fish with a miller - dieker / lissencephaly region probe ( vysis , abbott laboratories , abbott park , il , usa ) was performed on the same g - banded metaphase chromosomes according to the manufacturer 's instructions . the mds probe signal ( 17p13.3 ) was detected on chromosome 12qter , indicating an unbalanced segregation of t(12;17 ) ( fig . further characterization of the size and boundaries of the cytogenetic abnormalities of the proband was performed using human genome cgh microarray kit 244 ( agilent technologies , palo alto , ca , usa ) , which consists of approximately 244,000 arrayed 60-base oligonucleotide - probes that span both coding and non - coding sequences with an average spatial resolution of about 15 kb . array cgh showed about a 4.6-mb deletion involving 17p13.3 , but it did not show duplication at 12q [ arr17p13.3p13.2 ( 28,969 - 4,653,156)1 pat ] ( fig . our case showed a deletion involving 17p13.3pter and a severe clinical phenotype of mds , including lissencephaly with band heterotopia , corpus callosum agenesis , peculiar facial morphology , cardiac defects , and limb anomalies . the deletion in 17p13.3pter in our case included simultaneous deletion of the platelet - activating factor acetylhydrolase 1b , regulatory subunit 1 ( pafah1b1 ) gene ( previously called lis1 ) , and the tyrosine 3-monooxygenase / tryptophan 5-monooxygenase activation protein , epsilon polypeptide ( ywhae ) . lissencephaly is associated with the loss or mutation of the pafah1b1 gene , which contributes to neuronal migration during embryological development , and additional loss of the v - crk sarcoma virus ct10 oncogene homolog ( avian ) ( crk ) and ywhae genes . these genes are telomeric to the pafah1b1 gene and contribute to cortical development and the severity of mds . reported a case of mds with periventricular nodular heterotopia caused by an unbalanced t(12;17 ) ( q24.31;p13.3 ) translocation , which showed a 3.7-mb deletion at 17p13.3pter and a duplication of about 11 mb at 12q24.31qter . the phenotypes of our case were similar to those of the case reported by grosso et al . cortical heterotopias are relatively uncommon in mds , but if present , they are usually in the form of subcortical heterotopias . however , the ywhae gene has been recently reported to contribute to periventricular heterotopic malformation . our case showed no definite duplication of 12q in the high - resolution array cgh , and there were no recognizable phenotypic features of a partial duplication of 12q24.33qter . a phenotype for trisomy 12q has been described on the basis of the size differences of the duplicated 12q . chromosome 12q duplication syndrome has common clinical features , including mild development delay , mild mental retardation , broad forehead , simplified ear helices , small mouth , and thin lips . partial trisomy of 12q24.33qter with a 1.3-mb chromosome imbalance derived from a familial t(12;17)(q24.33;q25.3 ) showed only some mild phenotypic similarities with the features of the 12q duplication syndrome . sathanoori et al .   reported the smallest cryptic duplication ( ~423 kb ) of 12q24.33qter , in which about 37 genes were found to be listed in the human genome database ( ensembl v37 ) . the genes included golga3 , chfr , and zinc finger genes ( znf605 , znf26 , znf84 , znf140 , znf10 , and znf268 ) . however , no important genes in the 12q24.33qter region were identified in our case . in comparison with bacterial artificial chromosome ( bac ) arrays , the high - resolution oligonucleotide arrays used in our case offer a much greater probe density for better detection of smaller genomic imbalances with a functional lower limit of 36 kb . thus , chromosomal alternations smaller than ~36 kb may be theoretically undetectable by array cgh ( agilent technologies ) . in our case , even if the cryptic region of 12q is not detected by high - resolution array cgh , the chromosomal alterations would be considered benign or clinically insignificant because of the absence of recognizable phenotypic features of a partial duplication of 12q24.33qter in the karyotype . moreover , a consensus statement for array cgh recently described that the smallest known recurrent pathogenic microdeletion syndromes are ~500 kb or larger , and array cgh , with a lower limit of resolution of ~400 kb throughout the genome , will reliably identify all known recurrent pathogenic microdeletion and microduplication syndromes [ 15 , 16 ] . in addition , although cytogenetic events might appear to be balanced at the microscopic level of resolution , many such events have submicroscopic imbalances . in our case , the mds caused by a balanced translocation of t(12;17 ) was difficult to detect and would have gone unnoticed without the previous history of recurrent lissencephaly . the use of fish on giemsa - trypsin - leishman ( gtl ) banded metaphase chromosomes ( sequential g - banding and fish ) is effective for defining the cryptic translocation . moreover , array cgh has enabled further delineation of the clinical spectrum of known chromosomal abnormalities and the identification of novel , recurrent genetic imbalances . in summary , this is a rare mds case derived from a parental balanced translocation confirmed by genomic array cgh and fish . for this reason , the deletion of 17p in mds in the proband should be not interpreted as a de novo deletion without a parental study , especially in parents with a history of recurrent pregnancy loss . accurate genetic counseling can be offered to the family in cases where there is a potential risk of recurrent lissencephaly in the next pregnancy . the combined use of array cgh and fish analysis is a powerful tool for the diagnosis of genetic diseases and can reveal unexpected genomic imbalances .
miller - dieker syndrome involves a severe type of lissencephaly , which is caused by defects in the lissencephaly gene ( lis1 ) . 
 we report the case of a female infant with der(17)t(12;17)(q24.33;p13.3)pat caused by an unbalanced segregation of the parental balanced translocation of 17p with other chromosomes . 
 the proband presented with facial dysmorphism , arthrogryposis , and intrauterine growth retardation . 
 most cases of miller - dieker syndrome have a de novo deletion involving 17p13.3 . 
 when miller - dieker syndrome is caused by an unbalanced translocation , mild - to - severe phenotypes occur according to the extension of the involved partner chromosome . however , a pure partial monosomy derived from a paternal balanced translocation is relatively rare . in this case 
 , the submicroscopic cryptic deletion in the proband was initially elucidated by fish , and karyotype analysis did not reveal additional chromosome abnormalities such as translocation . however , a family history of recurrent pregnancy abnormalities strongly suggested familial translocation . 
 sequential g - banding and fish analysis of the father 's chromosomes showed that the segment of 17p13.3pter was attached to the 12qter . 
 thus , we report a case that showed resemblance to the findings in cases of a nearly pure 17p deletion , derived from t(12;17 ) , and delineated by whole genome array comparative genomic hybridization ( cgh ) . if such cases are incorrectly diagnosed as miller - dieker syndrome caused by de novo 17p13.3 deletion , the resultant improper genetic counseling may make it difficult to exactly predict the potential risk of recurrent lissencephaly for successive pregnancies .