hypothalamic hamartoma ( hh ) is a congenital malformation that usually originates close to the tuber cinereum 
 and mamillary bodies ; it has a sessile or pedunculated attachment , extends into the interpeduncular cistern and 
 sometimes bulges into the floor of the third ventricle ( 1 , 2 ) . hh is diagnosed based on magnetic resonance imaging ( mri ) and histological 
 findings ; it is often associated with central precocious puberty ( cpp ) , gelastic seizures , abnormal behavior and 
 mental retardation ( 2 , 3 ) . cpp in hh patients may start at a very young age , in some cases even at birth ( 3 , 4 ) . treatment with a gonadotropin - releasing hormone ( gnrh ) 
 analogue is reportedly effective in patients with gonadotropin - dependent precocious puberty and hh ( 5 , 6 ) . his length was 51 cm and his 
 weight was 3,500 g. he had gelastic seizures starting in the neonatal period , but his parents did not 
 recognize them . at the age of 3 yr and 8 mo , he underwent an eeg examination , and epilepsy was diagnosed . on 
 admission to our hospital , his height was 102.4 cm ( + 0.71 sd)and his weight was 14.8 kg ( 0.35 sd ) . the tumor mass was sessile and 1.2  
 1.5 cm in diameter , and it involved the hypothalamus and distorted the third ventricle ( fig . 1 mri findings ( t1-weighted sagittal images ) from cases 1 ( a ) and 2 ( b ) . the lesions ( 1.2  1.5 cm in 
 case 1 ; 2.0  2.5 cm in case 2 ) , which are protruding into the interpeduncular cistern , are isointense 
 to gray matter and distort the third ventricle . ) . the patient was treated with antiepileptic drugs ( valproic acid and clonazepam ) , but his epileptic 
 attacks remained intractable . at the age of 4 yr and 11 mo , he was treated with a -knife , and his drop 
 attacks disappeared , but his gelastic seizures did not change . later , a hormonal examination showed a high 
 serum testosterone level ( 149.0 ng / dl ) . on a subsequent lh - rh loading test , his lh and fsh responses showed a 
 pubertal pattern ( table 1 ) . at the age of 6 yr , enlargement of the 
 testes and penis was observed ; his testicular volume was 5 ml , penis tanner stage ii and bone age ( ba ) was 8 
 yr at a chronological age ( ca ) of 6 yr and 3 mo . he was treated with a gnrh analogue ( 40 g / kg ) every 4 wk for 
 7 mo , starting at 6 yr and 4 mo of age . after 3 mo of gnrh analogue treatment , the lh , fsh and testosterone 
 levels were suppressed . at the age of 7 yr , he was treated with partial surgical removal of the hh because of 
 intractable seizures . histopathological examination showed that the resected tumor tissue was composed of 
 numerous small neurons , as well as mature ganglion cells and glial cells . the small neurons had scanty 
 cytoplasm and the other cells were immature with a partially atrophic pattern . immunohistochemical staining with lh - rh antibody was positive in neurons and endothelial cells of capillary 
 walls ( fig . 2 histopathology of cases 1 ( a ) and 2 ( b ) . left ( a ) h.e . right ( a ) lh - rh stain ( arrow shows 
 lh - rh positive area ) . after the operation , the epileptic attacks disappeared , and gnrh analogue treatment was restarted at 
 a ca of 7 yr and 7 mo because his pubertal symptoms reappeared . 3 growth charts for cases 1 ( a ) and 2 ( b ) .. his intelligence quotient ( iq ) score on the wechsler intelligence scale for children ( wisc ) improved 
 from 66 ( verbal iq ( viq ) , 68 ; performance iq ( piq),71 ) to 86 ( viq 82 , piq 93 ) after the operation and gnrh 
 analogue treatment . table 1 laboratory findings of cases 1 and 2case 1(at the age of 5 yr and 10 mo)(normal range)acth41.1 pg / ml(1060)cortisol8.6 g / dl(4.524)tsh3.78 iu / ml(0.534.43)ft33.98 pg / ml(2.284.11)ft41.06 ng / dl(0.942.00)testosterone149.0 ng / dl(<5.0)igf-1225 ng / ml(50290)lh - rh loading test(at the age of 6 yr and 3 mo)(normal range)lh ( miu / ml)fsh ( miu / ml)before3.7 ( 0.020.44)5.6 ( 0.182.58)after 30 min24.57.9after 60 min25.09.7after 90 min20.98.9after 120 min17.08.8(at the age of 6 yr and 10 mo)lh0.4 miu / mlfsh<0.4 miu / mltestosterone<5.0 ng / dlcase 2(at the age of 1 yr and 6 mo)(normal range)acth42.0 pg / ml(1060)cortisol14.4 g / dl(4.524)tsh2.42 iu / ml(0.534.43)ft32.41 pg / ml(2.284.11)ft41.17 ng / dl(0.942.00)testosterone459.3 ng / dl(<5.0)igf-1253 ng / ml(22160)lh - rh loading test(at the age of 1 yr and 7 mo)(normal range)lh ( miu / ml)fsh ( miu / ml)before1.9 ( 0.020.44)4.4 ( 0.182.58)after 30 min24.67.7after 60 min20.88.4after 90 min17.18.6after 120 min13.98.5(at the age of 3 yr and 10 mo)lh0.3 miu / mlfsh<0.5 miu / mltestosterone<5.0 ng / dl 
   mri findings ( t1-weighted sagittal images ) from cases 1 ( a ) and 2 ( b ) . the lesions ( 1.2  1.5 cm in 
 case 1 ; 2.0  2.5 cm in case 2 ) , which are protruding into the interpeduncular cistern , are isointense 
 to gray matter and distort the third ventricle . histopathology of cases 1 ( a ) and 2 ( b ) . left ( a ) h.e . right ( a ) lh - rh stain ( arrow shows 
 lh - rh positive area ) . this patient was a boy at 4 yr and 10 mo of age . at the age of 7 mo , his height and weight growth accelerated 
 and pubic hair appeared . mri showed an isointense hypothalamic mass of the tuber cinereum , and hh was 
 diagnosed . the mass was sessile and 2.0  2.5 cm in diameter , and it involved the hypothalamus and distorted 
 the third ventricle ( fig . 1 ( b ) ) . the patient did not show overt 
 epileptic attacks , but a spike in the right central region was detected on eeg . antiepileptic drugs were not 
 prescribed . at a ca of 1 yr and 6 mo , he showed behavioral abnormalities , including hyperactivity and 
 aggression , and his height and weight were 91.8 cm ( + 3.32 sd ) and 17.2 kg ( + 5.82 sd ) , respectively . his testes 
 were enlarged ( 56 ml ) , pubic hair tanner stage was ii , serum testosterone levels were elevated ( 459.3 ng / ml ) 
 and ba was 7 yr . his serum lh and fsh levels were in the pubertal range both before and after the lh - rh 
 loading test ( table 1 ) . cpp was diagnosed , and he was started on 
 treatment with a gnrh analogue ( 50 g / kg ) every 4 wk . three months after gnrh analogue treatment , his 
 gonadotropin and testosterone levels were suppressed . the patien s physical pubertal signs also showed gradual 
 suppression . at the age of 1 yr and 11 mo , surgery to partially remove the hh was performed . histopathology 
 showed atrophic and irregular round neurons , with some parts consisting of mature ganglion cells . gfap(glial 
 fibrillary acidic protein ) positive astrocytes showed no significant proliferative or heteromorphic 
 characteristics . 3 ( b ) . after surgical removal of the hh and gnrh analogue 
 treatment , his abnormal behavior and dq ( developmental quotient)/iq scores were improved , from a dq of 86 by 
 the tsumori inage test before the operation to an iq of 116 by the tk binet intelligence test after the 
 operation and gnrh analog treatment . his length was 51 cm and his 
 weight was 3,500 g. he had gelastic seizures starting in the neonatal period , but his parents did not 
 recognize them . at the age of 3 yr and 8 mo , he underwent an eeg examination , and epilepsy was diagnosed . on 
 admission to our hospital , his height was 102.4 cm ( + 0.71 sd)and his weight was 14.8 kg ( 0.35 sd ) . the tumor mass was sessile and 1.2  
 1.5 cm in diameter , and it involved the hypothalamus and distorted the third ventricle ( fig . 1 mri findings ( t1-weighted sagittal images ) from cases 1 ( a ) and 2 ( b ) . the lesions ( 1.2  1.5 cm in 
 case 1 ; 2.0  2.5 cm in case 2 ) , which are protruding into the interpeduncular cistern , are isointense 
 to gray matter and distort the third ventricle . ) . the patient was treated with antiepileptic drugs ( valproic acid and clonazepam ) , but his epileptic 
 attacks remained intractable . at the age of 4 yr and 11 mo , he was treated with a -knife , and his drop 
 attacks disappeared , but his gelastic seizures did not change . later , a hormonal examination showed a high 
 serum testosterone level ( 149.0 ng / dl ) . on a subsequent lh - rh loading test , his lh and fsh responses showed a 
 pubertal pattern ( table 1 ) . at the age of 6 yr , enlargement of the 
 testes and penis was observed ; his testicular volume was 5 ml , penis tanner stage ii and bone age ( ba ) was 8 
 yr at a chronological age ( ca ) of 6 yr and 3 mo . he was treated with a gnrh analogue ( 40 g / kg ) every 4 wk for 
 7 mo , starting at 6 yr and 4 mo of age . after 3 mo of gnrh analogue treatment , the lh , fsh and testosterone 
 levels were suppressed . at the age of 7 yr , he was treated with partial surgical removal of the hh because of 
 intractable seizures . histopathological examination showed that the resected tumor tissue was composed of 
 numerous small neurons , as well as mature ganglion cells and glial cells . the small neurons had scanty 
 cytoplasm and the other cells were immature with a partially atrophic pattern . immunohistochemical staining with lh - rh antibody was positive in neurons and endothelial cells of capillary 
 walls ( fig . 2 histopathology of cases 1 ( a ) and 2 ( b ) . left ( a ) h.e . right ( a ) lh - rh stain ( arrow shows 
 lh - rh positive area ) . after the operation , the epileptic attacks disappeared , and gnrh analogue treatment was restarted at 
 a ca of 7 yr and 7 mo because his pubertal symptoms reappeared . 3 growth charts for cases 1 ( a ) and 2 ( b ) .. his intelligence quotient ( iq ) score on the wechsler intelligence scale for children ( wisc ) improved 
 from 66 ( verbal iq ( viq ) , 68 ; performance iq ( piq),71 ) to 86 ( viq 82 , piq 93 ) after the operation and gnrh 
 analogue treatment . table 1 laboratory findings of cases 1 and 2case 1(at the age of 5 yr and 10 mo)(normal range)acth41.1 pg / ml(1060)cortisol8.6 g / dl(4.524)tsh3.78 iu / ml(0.534.43)ft33.98 pg / ml(2.284.11)ft41.06 ng / dl(0.942.00)testosterone149.0 ng / dl(<5.0)igf-1225 ng / ml(50290)lh - rh loading test(at the age of 6 yr and 3 mo)(normal range)lh ( miu / ml)fsh ( miu / ml)before3.7 ( 0.020.44)5.6 ( 0.182.58)after 30 min24.57.9after 60 min25.09.7after 90 min20.98.9after 120 min17.08.8(at the age of 6 yr and 10 mo)lh0.4 miu / mlfsh<0.4 miu / mltestosterone<5.0 ng / dlcase 2(at the age of 1 yr and 6 mo)(normal range)acth42.0 pg / ml(1060)cortisol14.4 g / dl(4.524)tsh2.42 iu / ml(0.534.43)ft32.41 pg / ml(2.284.11)ft41.17 ng / dl(0.942.00)testosterone459.3 ng / dl(<5.0)igf-1253 ng / ml(22160)lh - rh loading test(at the age of 1 yr and 7 mo)(normal range)lh ( miu / ml)fsh ( miu / ml)before1.9 ( 0.020.44)4.4 ( 0.182.58)after 30 min24.67.7after 60 min20.88.4after 90 min17.18.6after 120 min13.98.5(at the age of 3 yr and 10 mo)lh0.3 miu / mlfsh<0.5 miu / mltestosterone<5.0 ng / dl 
   mri findings ( t1-weighted sagittal images ) from cases 1 ( a ) and 2 ( b ) . the lesions ( 1.2  1.5 cm in 
 case 1 ; 2.0  2.5 cm in case 2 ) , which are protruding into the interpeduncular cistern , are isointense 
 to gray matter and distort the third ventricle . histopathology of cases 1 ( a ) and 2 ( b ) . left ( a ) h.e . right ( a ) lh - rh stain ( arrow shows 
 lh - rh positive area ) . this patient was a boy at 4 yr and 10 mo of age . at the age of 7 mo , his height and weight growth accelerated 
 and pubic hair appeared . mri showed an isointense hypothalamic mass of the tuber cinereum , and hh was 
 diagnosed . the mass was sessile and 2.0  2.5 cm in diameter , and it involved the hypothalamus and distorted 
 the third ventricle ( fig . 1 ( b ) ) . the patient did not show overt 
 epileptic attacks , but a spike in the right central region was detected on eeg . antiepileptic drugs were not 
 prescribed . at a ca of 1 yr and 6 mo , he showed behavioral abnormalities , including hyperactivity and 
 aggression , and his height and weight were 91.8 cm ( + 3.32 sd ) and 17.2 kg ( + 5.82 sd ) , respectively . his testes 
 were enlarged ( 56 ml ) , pubic hair tanner stage was ii , serum testosterone levels were elevated ( 459.3 ng / ml ) 
 and ba was 7 yr . his serum lh and fsh levels were in the pubertal range both before and after the lh - rh 
 loading test ( table 1 ) . cpp was diagnosed , and he was started on 
 treatment with a gnrh analogue ( 50 g / kg ) every 4 wk . three months after gnrh analogue treatment , his 
 gonadotropin and testosterone levels were suppressed . the patien s physical pubertal signs also showed gradual 
 suppression . at the age of 1 yr and 11 mo , surgery to partially remove the hh was performed . histopathology 
 showed atrophic and irregular round neurons , with some parts consisting of mature ganglion cells . gfap(glial 
 fibrillary acidic protein ) positive astrocytes showed no significant proliferative or heteromorphic 
 characteristics . after surgical removal of the hh and gnrh analogue 
 treatment , his abnormal behavior and dq ( developmental quotient)/iq scores were improved , from a dq of 86 by 
 the tsumori inage test before the operation to an iq of 116 by the tk binet intelligence test after the 
 operation and gnrh analog treatment . two cases of cpp associated with hh diagnosed by mri and histological findings are described in this report . first described the syndrome of gelastic seizures , hh and mental retardation 
 and estimated its prevalence to be 1 in 50,000 to 100,000 ( 7 ) . the most 
 probable signs indicating a diagnosis of hh include ( i ) precocious onset of pubertal development at a very young 
 age , ( ii ) hormonal findings compatible with cpp , ( iii ) demonstration of an isointense tumor in a typical 
 location showing no gadolinium enhancement on mri and ( iv ) gelastic seizures , abnormal behavior and mental 
 retardation ( 8,9,10 ) . cpp may be associated with hamartoma , glioma , neuroblastoma , 
 tuberculosis meningitis , craniopharyngioma and arachnoid cyst . mri is a necessary diagnostic tool for detecting cpp 
 with hh . in the present cases , mri showed a nonenhancing , stable isointense lesion on t1-weighted 
 images that was hyperintense or isointense on t2-weighted images as compared with gray matter . the 
 differential diagnosis includes ganglioglioma , astrocytoma , craniopharyngioma , suprasellar germinoma and 
 lymphoma ( 2 ) . histologically , hh usually shows low cell density with 
 irregularly structured groups of multipolar ganglionoid cells and myelinated fibers arranged in small bundles . immunohistochemical studies 
 showed positive staining for neuron - specific enolase , synaptophysin and neurofilament protein ; other lh - rh 
 granules have also been detected by staining of specimens from cpp patients with hh ( 2 ) . the mechanism by which hh induces cpp is unknown , but it has been speculated that local pressure , abnormal 
 neuronal connections , surgical lesions , independent endocrine activity or combinations of these factors may play 
 a role ( 2 , 12 , 13 ) . other authors have suggested activation of endogenous lh - rh secretion 
 via astroglial - derived factors as a possible mechanism of cpp(6 ) . in some cases , reviewed the relationship between hh size and the occurrence of seizures and demonstrated that 
 patients with a hamartoma less than 10 mm in diameter did not have seizures . in contrast , all patients with 
 hamartomas of 25 mm or larger had seizures ( 14 ) . proposed classifying hh into four groups ( ia , ib , iia and iib ) based on topographical and 
 clinical data . in type ii , the hh is large , the mass has a sessile attachment and there is clear distortion of 
 the third ventricle . cpp patients 
 with hh may have gelastic and mixed seizures , mental retardation and behavioral abnormalities . in types ia and 
 ib , hh is associated with cpp without seizures ( 2 ) . demonstrated that small pedunculated hhs were associated with cpp , while large sessile hhs were 
 associated with seizures ( 15 ) . classified 
 hh into two categories , the parahypothalamic and intrahypothalamic types , based on mri findings ; they found that 
 the parahypothalamic type was associated with isolated cpp , whereas the intrahypothalamic type was associated 
 with seizures , developmental delay and cpp ( 16 ) . proposed classifying hh into four types based on anatomy ( 17 ) . in the present cases , the hhs were sessile and associated with cpp . the hh was 1.2  1.5 cm in 
 the case with gelastic seizures and 2.0  2.5 cm in the case with eeg abnormalities but no seizures . they would be categorized as type ii according to 
 valdueza et al.(2 ) and as the intrahypothalamic type 
 according to arita et al . ( 16 ) , but both cases had cpp , 
 and the second had no seizures . because the pathomechanisms of the clinical manifestations of hh are still 
 unclear and confusion arises from the vagueness of the criteria for the topology of hh , it was difficult to 
 determine a topology / symptom relationship ( 16 ) . hh frequently occurs with a variety of cognitive impairments and behavioral abnormalities ( 3 , 8,9,10 ) . the behavioral abnormalities might 
 be multifactorial in origin due to psychosocial difficulties , hospitalization , mental retardation , epilepsy or 
 drug effects . episodes of severe rage , a type of behavioral abnormality , were not associated with seizures and 
 may have been related to the lesion . treatment with a gnrh analogue improves hormonal laboratory findings and the height prognosis of hh patients 
 with cpp ( 18 , 19 ) . hh is not an 
 indication for surgical resection ; however , it may be indicated for patients with intractable seizures that 
 can not be controlled by anticonvulsants ( 15 , 20 , 21 ) . some authors have reported dramatic 
 improvements in behavior and cognition following hh resection ( 9 , 10 ) . others have reported that complete hh resection in cpp patients 
 completely cures cpp(22 , 23 ) . 
 furthermore , there are also reports indicating that treatments with a gnrh analogue for hh with cpp decrease 
 tumor size and suppress gelastic seizures ; however , the underlying mechanisms were not clarified(24 , 25 ) . of the two hh cases with cpp presented herein , the first was treated with a -knife , surgical removal of the 
 hh , and then gnrh analogue therapy for cpp . this patient s iq score increased from 66 to 86 after 7 mo of gnrh 
 analogue treatment . this patient s dq score before starting gnrh analogue therapy was 
 86 ( ca of 1 yr 6 mo ) , and after surgical removal of the hh followed by gnrh analogue therapy , his iq was 116 ( ca 
 of 4 yr 8 mo ) . it appears that gnrh analogue therapy and surgical hh removal improved the dq / iq score in this 
 patient , as well as his abnormal movements . estrogens may have a proconvulsant effect , and treatment with estrogens has been reported 
 to be associated with behavioral changes in animals , including stereotypical recurrent behaviors ( 26 , 27 ) . gnrh analogue therapy has 
 been reported to slightly decrease problematic behavior and improve functioning ( 28 ) .
hypothalamic hamartoma ( hh ) is a congenital malformation diagnosed based on magnetic resonance imaging ( mri ) 
 and histological findings ; it is often associated with central precocious puberty ( cpp ) , gelastic seizures , 
 abnormal behavior and mental retardation . in the present paper , 
 we report our retrospective hypothesis that 
 there is a relationship between symptoms and therapy , as well as the treatment for hh , and describe two cases 
 of hh associated with cpp . 
 both cases had sessile masses located in the interpeduncular cistern , with 
 extension to the hypothalamus on mri ( 1.2  1.5 cm and 2.0  2.5 cm , respectively ) . 
 the first case had 
 intractable seizures , while the second had no seizures with paroxysmal discharge . in both patients , 
 the 
 hamartomas were partially removed , by -knife and surgical operation in the first case and surgically in the 
 second , and a gonadotropin releasing hormone ( gnrh ) analogue was prescribed . 
 one case showed improvement of 
 both intelligence quotient ( iq ) score and seizures , and the other showed improvements in iq and abnormal 
 behavior . 
 it was difficult to determine any topology / symptom relationships . 
 surgery and gnrh analogue 
 treatment can alleviate seizures , abnormal behavior and mental retardation associated with hh .