document: congenital adrenal hyperplasia ( cah ) describes a group of inherited autosomal recessive disorders that cause a deficiency in an adrenal enzyme resulting in altered cortisol and aldosterone secretion . 
   the most frequent cah variant , accounting for 95% of all affected patients , is 21-hydroxylase deficiency ( 21-ohd ) and is caused by inactivating mutations in the 21-hydroxylase gene ( cyp21a2 ) . 
   the deficiency of 21-hydroxylase causes a decrease in negative feedback to the hypothalamic - pituitary - adrenal ( hpa ) axis , and subsequent hyperplasia of the adrenal gland . 
   cortisol and aldosterone precursors are subsequently diverted to androgens , causing increased virilization and a chronic hyperandrogenic state . 
   there are different clinical forms of cah associated with 21-ohd : classical cah , the most severe form comprises both salt - wasting ( sw ) and simple virilizing ( sv ) forms , and the non - classical ( nc ) form which may be asymptomatic or associated with symptoms of postnatal or even adult onset hyperandrogenism . 
   several studies have suggested high concordance rates between genotype and phenotype in patients with the classic form of cah . 
   treatment of cah consists of replacement of glucocorticoids and , when necessary , mineralocorticoids to prevent adrenal crises and to suppress the abnormal secretion of androgens and steroid precursors from the adrenal cortex . 
   conventional glucocorticoid replacement can not , however , mimic the natural circadian rhythms of cortisol release . even in adequately treated patients , 
   there are reports of clinical evidence of both over - suppression with glucocorticoid including iatrogenic cushing 's syndrome , obesity , and decreasing growth velocity and under - suppression including virilization , menstrual disorders and infertility , growth suppression , and development of adrenal tumors . 
   cah constitutes an interesting natural model for studying interactions between hormones and the brain . until now , only a few studies described brain magnetic resonance imaging ( mri ) abnormalities in cah patients . 
   hormonal imbalances during early development and exposure to excess exogenous glucocorticoids are the most probable explanations for these mri findings.[711 ] in the present study , we investigated the frequency of white matter changes and temporal lobe structures dysgenesis in patients with cah due to 21-ohd . 
   we studied 26 patients with cah due to 21-ohd ( 11 males and 15 females , mean age  sd = 27.4  8.2 years , range = 16.5 - 48 years ) , who were followed at the department of endocrinology in mahdia and sfax , in tunisia . 
   this sample includes all patients with cah , aged more than 16 years and regularly followed at these two clinics since 1982 . 
   the diagnosis of cah was based on clinical and biochemical criteria ( i.e. , elevated levels of 17-hydroxyprogesterone ( 17-ohp ) and androstenedione , acth stimulation test ) . 
   ten patients ( 6 m , 4 f ) had the sw form of cah . they had been diagnosed in their first year of life and had been treated , from the time of diagnosis , with glucocorticoids and mineralocorticoids . 
   eight patients ( 5 m , 3 f , age at diagnosis : between birth and 6 years ) were diagnosed as classical sv patients . in the other eight patients ( women only in this group ) , the nc form was diagnosed between 15 and 44 years of age . 
   twenty - one patients were started on a regimen of hydrocortisone ( hc ) , given 2 or 3 times daily , whereas the remaining five patients ( three with the nc form and two with the classic sv form ) were treated with dexamethasone ( once daily ) . 
   salt wasters were treated with 27.9  9.6 mg / m per day of hc the first 2 years of life , and the doses were decreased to 17.6  6.6 mg / m per day during childhood . 
   daily doses of hc in patients with classical and nc forms were respectively , 17.3  4.6 mg / m and 16.04  3.4 mg / m during adulthood . for dexamethasone , 
   clinical and brain magnetic resonance imaging findings in 26 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency the adequacy of therapy was monitored periodically on the basis of clinical and laboratory data , in accordance with current guidelines . 
   patients were classified as under adequate hormonal control if 50% or more of the total serum androgen levels were within normal limits for age or if 50% or more of the baseline serum 17-ohp concentrations were 2.0 - 10 ng / ml ( 6 - 30 
   the mean duration of the follow - up period was 18.5  9.3 ( range 3 - 41.5 ) years . 
   seven patients ( five with the sw form and two with the sv form ) had experienced a sw adrenal crisis in the neonatal period . one female patient ( patient 
   she was started on l - thyroxine 10 g / kg per day at the age of 6 months , but she was irregular in follow - up and was not compliant with treatment . 
   4 ) with the sw form developed hypertension at 8 years of age and responded well to nifedipine . 
   detailed investigations ( renal doppler ultrasound , adrenal ct scan , urinary metanephrine , 11-deoxycortisol , and aldosterone concentrations ) failed to detect any cause for secondary hypertension , and a diagnosis of essential hypertension was made . 
   all our patients or their parents gave their informed consent to participate in the study and underwent neurological examination and brain mri . 
   the imaging protocol included axial and sagittal spin - echo ( se ) t1-weighted [ repetition time ( tr ) 550 ms , echo time ( te ) 15 ms , flip angle 90 ] , axial and coronal enhanced t1-weighted ( tr 550 ms , te 15 ms , flip angle 90 , axial fast se ( fse ) t2-weighted ( tr 5000 ms , te 94 ms , flip angle 90 ) , axial proton - density ( pd ) t2-weighted ( tr 2500 ms , te 18 ms , flip angle 90 ) , and coronal fluid - attenuated inversion recovery [ flair ; tr 7500 ms , te 94 ms , inversion time ( ti ) 2200 , flip angle 90 ] sections . 
   white matter changes were defined as areas of increased signal intensity on intermediate and t2-weighted sequences . 
   thin coronal mri slices , perpendicular to the axis of the hippocampus were used for determining hippocampal dysplasia ( hippocampus with distorted anatomy , small volume , disturbed internal architecture , and increased signal on t2 and flair images ) . 
   amygdala was regarded as dysplastic if it was smaller than the contralateral side , if increased signal on t2 and flair sequences was observed , or both . 
   further investigations , including viral serologies , amino acid profile , organic acid profile , lactate , ceruloplasmin , lumbar puncture and arylsulfatase a activity , were performed in a16.5-year - old patient ( patient no . 
   4 ) with the classical sw form of cah and who presented with hypertension , obesity , mental decline , tremor , cerebellar syndrome , white matter hyperintensities , and agenesis of the corpus callosum . 
   we studied 26 patients with cah due to 21-ohd ( 11 males and 15 females , mean age  sd = 27.4  8.2 years , range = 16.5 - 48 years ) , who were followed at the department of endocrinology in mahdia and sfax , in tunisia . 
   this sample includes all patients with cah , aged more than 16 years and regularly followed at these two clinics since 1982 . 
   the diagnosis of cah was based on clinical and biochemical criteria ( i.e. , elevated levels of 17-hydroxyprogesterone ( 17-ohp ) and androstenedione , acth stimulation test ) . 
   ten patients ( 6 m , 4 f ) had the sw form of cah . they had been diagnosed in their first year of life and had been treated , from the time of diagnosis , with glucocorticoids and mineralocorticoids . 
   eight patients ( 5 m , 3 f , age at diagnosis : between birth and 6 years ) were diagnosed as classical sv patients . in the other eight patients ( women only in this group ) , the nc form was diagnosed between 15 and 44 years of age . 
   twenty - one patients were started on a regimen of hydrocortisone ( hc ) , given 2 or 3 times daily , whereas the remaining five patients ( three with the nc form and two with the classic sv form ) were treated with dexamethasone ( once daily ) . 
   salt wasters were treated with 27.9  9.6 mg / m per day of hc the first 2 years of life , and the doses were decreased to 17.6  6.6 mg / m per day during childhood . 
   daily doses of hc in patients with classical and nc forms were respectively , 17.3  4.6 mg / m and 16.04  3.4 mg / m during adulthood . for dexamethasone , 
   clinical and brain magnetic resonance imaging findings in 26 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency the adequacy of therapy was monitored periodically on the basis of clinical and laboratory data , in accordance with current guidelines . 
   patients were classified as under adequate hormonal control if 50% or more of the total serum androgen levels were within normal limits for age or if 50% or more of the baseline serum 17-ohp concentrations were 2.0 - 10 ng / ml ( 6 - 30 
   the mean duration of the follow - up period was 18.5  9.3 ( range 3 - 41.5 ) years . 
   seven patients ( five with the sw form and two with the sv form ) had experienced a sw adrenal crisis in the neonatal period . one female patient ( patient 
   she was started on l - thyroxine 10 g / kg per day at the age of 6 months , but she was irregular in follow - up and was not compliant with treatment . 
   4 ) with the sw form developed hypertension at 8 years of age and responded well to nifedipine . 
   detailed investigations ( renal doppler ultrasound , adrenal ct scan , urinary metanephrine , 11-deoxycortisol , and aldosterone concentrations ) failed to detect any cause for secondary hypertension , and a diagnosis of essential hypertension was made . 
   all our patients or their parents gave their informed consent to participate in the study and underwent neurological examination and brain mri . 
   all patients underwent neurological and mri examinations . the mri examination was performed with a 1 t. siemens magnetom impact system . 
   the imaging protocol included axial and sagittal spin - echo ( se ) t1-weighted [ repetition time ( tr ) 550 ms , echo time ( te ) 15 ms , flip angle 90 ] , axial and coronal enhanced t1-weighted ( tr 550 ms , te 15 ms , flip angle 90 , axial fast se ( fse ) t2-weighted ( tr 5000 ms , te 94 ms , flip angle 90 ) , axial proton - density ( pd ) t2-weighted ( tr 2500 ms , te 18 ms , flip angle 90 ) , and coronal fluid - attenuated inversion recovery [ flair ; tr 7500 ms , te 94 ms , inversion time ( ti ) 2200 , flip angle 90 ] sections . 
   white matter changes were defined as areas of increased signal intensity on intermediate and t2-weighted sequences . 
   thin coronal mri slices , perpendicular to the axis of the hippocampus were used for determining hippocampal dysplasia ( hippocampus with distorted anatomy , small volume , disturbed internal architecture , and increased signal on t2 and flair images ) . 
   amygdala was regarded as dysplastic if it was smaller than the contralateral side , if increased signal on t2 and flair sequences was observed , or both . 
   further investigations , including viral serologies , amino acid profile , organic acid profile , lactate , ceruloplasmin , lumbar puncture and arylsulfatase a activity , were performed in a16.5-year - old patient ( patient no . 
   4 ) with the classical sw form of cah and who presented with hypertension , obesity , mental decline , tremor , cerebellar syndrome , white matter hyperintensities , and agenesis of the corpus callosum . all these investigations revealed negative or normal results . 
   on neurological examination , mental retardation was evident in three patients ( patient nos . 4 , 6 and 23 ) . 
   on intellectual quotient test , it was moderate in patient nos . 4 and 6 ( both had developed salt losing crisis during the neonatal period ) and profound in patient no . 23 
   other neurological signs included postural and action tremor in two patients ( patient nos . 4 and 23 ) , 
   1 ) , and static and kinetic cerebellar syndrome in one patient ( patient no . 
   4 ) . at the time of inclusion in the study , mean morning baseline 17-ohp in serum for the whole cohort was 22.51 ng / ml ( range , 1.1 - 77 ) ; mean morning androstenedione levels were 5.25 ng / ml ( range , 1.6 - 24 ) and mean morning plasma acth levels were 118.31 pg / ml ( range , 6.5 - 537 ) . during the treatment period , 
   poor hormonal control , with elevation of 50% or more of 4-androstenedione and 17-ohp serum measurements , was present in 16 patients ( 61.5% ) . 
   these were chronically non - compliant patients , mainly because of ignorance and lack of understanding . the remaining patient ( patient no . 
   eleven patients ( five males and six females , 42.3% ) showed mri abnormalities : one patient was over - treated ( patient no . 
   8) , two patients had good hormonal control ( patient nos . 13 and 15 ) and eight patients were poorly controlled due to non - compliance with their medication . 
   eight patients ( seven with the classic form and one with the nc form ) evidenced white matter hyperintensities on t2-weighted and flair images . 
   these hyperintensities were located in periventricular regions in seven patients [ figure 1a ] and in cerebellar white matter in the remaining patient [ patient no . 
   11 ) with the classical sv form showed moderate right temporal lobe atrophy [ figure 3 ] . indeed 
   21 , hippocampus was globular in shape and its internal structures were not identified [ figure 5 ] . other mri findings included partially empty sella in one patient ( patient no . 
   25 ) and cortico - subcortical atrophy associated with complete agenesis of the corpus callosum in another patient [ patient no . 
   a ) t2-weighted axial mri sequence showing bilateral periventricular white matter hyperintensities and cortico - subcortical atrophy in a 16.5-year - old patient affected by swcah ( patient no . 
   4 ) t1-weighted sagittal mri sequence showing complete agenesis of the corpus callosum in a 16.50 year old patient affected by swcah ( patient no . 
   4 ) axial flair and t2 mri showing bilateral cerebellar white matter hyperintensities in a 21-year - old man affected by sw cah ( patient no . 
   1 ) axial t1-weighted image showing moderate atrophy in the right anterior temporal lobe in a 47.5-year - old man affected by simple virilizingcah ( patient no . 
   11 ) t2-weighted mri , coronal section , showing right hippocampal atrophy in a 36-year - old woman affected by non - classic cah ( patient no . 
   23 ) coronal t2-weighted mri in a 30.5-year - old woman affected by non - classic cah . 
   the right hippocampus is moderately round - shaped and its internal structures are not identified ( patient no . 
   on neurological examination , mental retardation was evident in three patients ( patient nos . 4 , 6 and 23 ) . 
   on intellectual quotient test , it was moderate in patient nos . 4 and 6 ( both had developed salt losing crisis during the neonatal period ) and profound in patient no . 23 
   other neurological signs included postural and action tremor in two patients ( patient nos . 4 and 23 ) , 
   1 ) , and static and kinetic cerebellar syndrome in one patient ( patient no . 
   at the time of inclusion in the study , mean morning baseline 17-ohp in serum for the whole cohort was 22.51 ng / ml ( range , 1.1 - 77 ) ; mean morning androstenedione levels were 5.25 ng / ml ( range , 1.6 - 24 ) and mean morning plasma acth levels were 118.31 pg / ml ( range , 6.5 - 537 ) . during the treatment period , nine patients ( 34.6% ) showed well - controlled cah . 
   poor hormonal control , with elevation of 50% or more of 4-androstenedione and 17-ohp serum measurements , was present in 16 patients ( 61.5% ) . 
   these were chronically non - compliant patients , mainly because of ignorance and lack of understanding . the remaining patient ( patient no . 
   eleven patients ( five males and six females , 42.3% ) showed mri abnormalities : one patient was over - treated ( patient no . 
   . 13 and 15 ) and eight patients were poorly controlled due to non - compliance with their medication . 
   eight patients ( seven with the classic form and one with the nc form ) evidenced white matter hyperintensities on t2-weighted and flair images . 
   these hyperintensities were located in periventricular regions in seven patients [ figure 1a ] and in cerebellar white matter in the remaining patient [ patient no . 
   11 ) with the classical sv form showed moderate right temporal lobe atrophy [ figure 3 ] . indeed 
   21 , hippocampus was globular in shape and its internal structures were not identified [ figure 5 ] . 
   25 ) and cortico - subcortical atrophy associated with complete agenesis of the corpus callosum in another patient [ patient no . 
   a ) t2-weighted axial mri sequence showing bilateral periventricular white matter hyperintensities and cortico - subcortical atrophy in a 16.5-year - old patient affected by swcah ( patient no . 
   4 ) t1-weighted sagittal mri sequence showing complete agenesis of the corpus callosum in a 16.50 year old patient affected by swcah ( patient no . 
   4 ) axial flair and t2 mri showing bilateral cerebellar white matter hyperintensities in a 21-year - old man affected by sw cah ( patient no . 
   1 ) axial t1-weighted image showing moderate atrophy in the right anterior temporal lobe in a 47.5-year - old man affected by simple virilizingcah ( patient no . 
   11 ) t2-weighted mri , coronal section , showing right hippocampal atrophy in a 36-year - old woman affected by non - classic cah ( patient no . 
   23 ) coronal t2-weighted mri in a 30.5-year - old woman affected by non - classic cah . 
   the right hippocampus is moderately round - shaped and its internal structures are not identified ( patient no . 
   our study provides evidence of an increased frequency of white matter abnormalities and temporal lobe structures dysgenesis in cah patients . in the past , only a few studies described brain mri abnormalities in cah.[711 ] table 2 summarizes the major results . 
   overall , these studies documented abnormalities affecting white matter signal , temporal lobe and amygdala structure and function . major previous reports of brain magnetic resonance imaging abnormalities related to congenital adrenal hyperplasia white matter hyperintensities , or leukoencephalopathy , related to cah are an interesting finding in this population . in a previous italian study , 
   disease phenotype does not seem to affect the frequency of such lesions , which may even be present in heterozygous carriers of cyp21 mutations . 
   brain white matter impairment in cah involve typically periventricular regions or , less frequently , cerebellar area as seen in one of our patients . 
   these signal changes are non - specific and without side prevalence,[79 ] but they differ from those due to ischemic causes , as the latter involve namely subcortical and deep structures . 
   white matter hyperintensities in cah are most often subclinical or , less frequently , associated with unremarkable neurological signs . in the present study , 
   the data in the literature concerning the clinical significance of white matter lesions are controversial . 
   it has been suggested that a  threshold  area of white matter lesions must be present before cognitive deficits are installed . 
   the mechanisms that could explain mri lesions in cah remain poorly understood . hormonal imbalance related to a deficiency of cortisol and aldosterone and an overproduction of 17-oh - progesterone and androgen would cause a destabilization of the myelin molecule leading to its degeneration . 
   in addition , exogenous glucocorticoids may alter the process of neuronal maturation and myelination by inhibiting the differentiation of oligodendrocyte precursors . 
   thus both , overdose and discontinuous therapy have been suggested as factors favoring the emergence of brain mri abnormalities . in our patients , 
   chronic hyperandrogenism , a result of non - compliance with treatment , may be the main mechanism involved in the genesis of brain mri abnormalities . 
   aldosterone is provided with a regulating effect on the arterial structure by stimulating fibroblast proliferation and collagen synthesis via direct activation of local receptors . in this 
   regard , aldosterone deficiency could induce changes of cerebral arterial structure , and , as consequence , a subclinical cerebral ischemia . 
   this ischemia could also be indirectly promoted by glucocorticoids that alter glucose and lipid metabolism and reduce platelet aggregability . in our study , 
   similarly , nass , et al . reported some cah patients with white matter lesions , with localizations that were typical of demyelinating diseases ( located in the corpus callosum and cerebellum ) . 
   have described a patient whose condition was diagnosed at birth as the sw subtype of cah in whom relapsing - remitting multiple sclerosis developed . 
   the fact that a susceptibility locus for multiple sclerosis is in the hla region that comprises the cyp21 genes suggests a possible genetic link between multiple sclerosis and cah . 
   the organizational effects refer to permanent changes in brain structure , organization or function in utero or during critical periods of development . 
   the activational effects tend to be transient and refer to the acute effects of circulating steroids during adulthood . 
   two structures are known to have many androgen and glucocorticoid receptors and are particularly susceptible to the effects of excess glucocorticoids : the hippocampus , a central neural substrate of declarative memory , and the amygdala , a key to emotional coding . 
   the hippocampus also plays an important role in the fine - tuning of the hpa axis by participating in its glucocorticoid negative feedback regulation . 
   alterations in amygdala function have been implicated in the pathophysiological characteristics of anxiety and depressive disorders in both adults and children . 
   the effect of hypercortisolism on the amygdala has not been systematically studied ; however , patients with classic cah , who have prenatal glucocorticoid deficiency with possible postnatal iatrogenic glucocorticoid excess , have smaller amygdala volume than healthy age - and sex - matched controls . cah female patients have also enhanced response to negative facial emotions ( anger and fear ) compared with neutral expressions . 
   animal studies and human studies of adult patients with chronic hypercortisolemia have shown that prolonged exposure to glucocorticoid excess could result in extensive hippocampus damage and permanent memory impairment . 
   the mechanisms leading to brain atrophy include impaired neurogenesis , reduction in neurotrophic factors and reduction in cerebral glucose metabolism . 
   interestingly , it has been suggested that at least some of the deleterious effects of prolonged hypercortisolemia on cognitive functioning and hippocampal volume are reversible . 
   our present study showed temporal lobe atrophy in one patient and hippocampal dysgenesis in two patients . 
   this study is the first one demonstrating hippocampal abnormalities on mr imaging in patients with cah , and it showed , also for the first time , brain mri abnormalities in patients with the nc form of cah . studies of cognitive function in cah patients have reported discrepant findings . 
   it was suggested that patients with the most severe form of cah and those who have experienced sw adrenal crises with abnormal electrolytes as neonates are at risk for cognitive impairement . in the present study , 
   the remaining one had the nc form , but also had an uncontrolled congenital hypothyroidism which may also contribute to his altered mental status . in conclusion , 
   brain mri abnormalities are an interesting finding in cah patients and could affect white matter signal and temporal lobe structures 
   . these abnormalities could be the consequence of hormonal imbalance during brain development and corticosteroid treatment . 
   more extensive studies are required to define better the relationships between brain involvement and different cah phenotypes and treatment regimens .
summary: background : congenital adrenal hyperplasia ( cah ) is an inherited recessive disorder of adrenal steroidogenesis . 
   the enzymes most commonly affected are 21-hydroxylase . 
   past reports suggested brain magnetic resonance imaging ( mri ) abnormalities in cah patients , affecting white matter signal , temporal lobe and amygdala structure and function.aims:in the present study , we aimed to investigate the frequency of white matter changes and temporal lobes structures dysgenesis in a population of patients having cah due to 21-hydroxylase deficiency.materials and methods : neurological examination and brain mri were performed in 26 patients.results:neurological examination revealed mental retardation in three patients , tremor in two patients , tendon reflexes asymmetry in one patient , and cerebellar syndrome in one patient . 
   eleven patients ( 42.3% ) showed mri abnormalities : eight of them had white matter hyperintensities , one patient had moderate atrophy in the right temporal , and hippocampal dysgenesis was found in the remaining two patients.conclusions:brain mri abnormalities in cah patients include white matter hyperintensities and temporal lobe structures dysgenesis . 
   the mechanisms involved seem related to hormonal imbalances during brain development and exposure to excess exogenous glucocorticoids . 
   clinical implications of such lesions remain unclear . 
   more extensive studies are required to define better the relationships between brain involvement and different cah phenotypes and treatment regimens .