to report a case of wolfram syndrome ( ws ) characterized by diabetes mellitus , diabetes insipidus , progressive optic atrophy , and  deafness . a 19-year - old female patient , a known case of diabetes mellitus type i from six years before , presented with progressive vision loss since four years earlier . ws should be considered a differential diagnosis in patients with diabetes mellitus who present with optic atrophy , and it is necessary to perform a hearing test as well as collecting 24-h urine output . wolfram syndrome ( ws ) is an autosomal recessive neurodegenerative disorder characterized by diabetes insipidus , diabetes mellitus ( non - autoimmune ) , optic atrophy , and deafness ( a set of conditions referred to as didmoad).1 , 2 , 3 the gene responsible for the ws , named wsf1 , encodes an endoplasmic reticulum membrane - embedded protein called wolframin that is expressed in pancreatic beta cells and neurons.4 , 5 , 6 the estimated prevalence of ws is 1 in 770,000 , and it is believed to occur in 1 of 150 patients with type 1 diabetes . affected patients usually develop insulin - requiring diabetes and optic atrophy in early childhood , and diabetes insipidus as they become teenagers or young adults . in ws patients with diabetes insipidus , not only does vasopressin neuron loss occur in the supraoptic nucleus , but there is also a defect in vasopressin precursor processing . other manifestations of ws include progressive sensorineural deafness , hydronephrosis ( due in part to the high urine flow in diabetes insipidus ) , and neurologic dysfunction . why severe insulin - requiring diabetes develops is not known ; immunologic factors do not appear to be important . affected individuals have a median life expectancy of 30 years , with early mortality credited to neurological disorders , urological abnormalities and infection . differential diagnosis and treatment are difficult due to the variable presentation of symptoms . in the present study , a 19-year - old female patient , a known case of type i diabetes mellitus from six years before , presented to a private ophthalmology office . her visual acuity reduced to 1/10 on both eyes . she had a history of nocturia and high urine output for five years , and after that , she had incontinency . in the previous two years , she had been avoiding difficulty and using self - intermittent catheterization four times a day . on ophthalmic examination , intraocular pressure was 15  mmhg in both eyes , and biomicroscopic examinations were completely normal . on fundoscopic examination , she had bilateral optic atrophy without diabetic retinopathy ( fig .  1 , fig .  2 ) . accordingly , ws was suspected by the ophthalmologist , who referred her to an endocrinologist . investigations revealed polyuria ( 14  l per day ) , hypernatremia ( 156  meq / l ) , and hyperglycemia ( 351  mg / dl ) . other laboratory values were : creatinine , 1.1  mg / dl ; urea nitrogen , 28  mg / dl ; k , 4.5  meq / l ; tsh , 2.5 a random urine analysis showed a urine specific gravity of 1.006 , and the results of 24-h urine collection obtained a urine specific gravity of 1.005 [ normal values : 1.0101.030 ] . it was suspected that there might be an underlying cause for diabetes insipidus , due to the presence of a low urine specific gravity subsequently , a urine and plasma osmolality was performed , which were 150 and 312  mmol / kg , respectively . there was no change either in urine specific gravity or urine osmolality before and after the water deprivation test . after nasal desmopressin administration , urine osmolality increased from 125  mosm / kg to 600  mosm / kg and serum osmolality increased from 281  mosm / kg to 328osm / kg . given to an increase in urine osmolality of more than 100% measured by the desmopression stimulation test a few days later , the volume of urine collected in 24  h was within acceptable range . a magnetic resonance imaging ( mri ) of the brain revealed the loss of the physiological hyperintense signal of the posterior pituitary gland ( bright spot ) on t1-weighted images , suggesting the diagnosis of central diabetes insipidus ( fig . an audiologic examination revealed neurosensory deafness , and audiometry showed a bilateral high - frequency sensorineural hearing loss . the bladder wall had a trabecular pattern , and the urinary tract was dilated on both sides . the patient 's sister had similar symptoms , but she did not cooperate for further evaluation . ws was first described in 1938 by wolfram and wagener as a hereditary syndrome characterized by diabetes mellitus and optic atrophy acquired early in life . subsequent reports added diabetes insipidus and deafness to the syndrome , which develop in approximately 73 and 62% of sufferers , respectively.3 , 12 the minimal criteria for diagnosis are juvenile - onset diabetes and optic atrophy ; however patients also present with additional complications , hence the acronym didmoad ( diabetes insipidus , diabetes mellitus , optic atrophy , and deafness ) is used . the diagnosis is established in individuals of all ages in whom two pathological wfs1 or cisd2 mutations are identified . diabetes mellitus is a key feature of ws , which is usually the first sign of the disease ( median age at diagnosis , 615 years ) , and optic atrophy ( median age at diagnosis 11 years ) . the mean age of presentation of diabetes mellitus has been reported to be 5    4 years . there are multiple differences between the presentation and course of autoimmune type 1 diabetes and diabetes of ws . namely , patients affected with ws have a low incidence of diabetic ketoacidosis at the time of diagnosis ( only 3% compared to 30% in type 1 diabetes ) , a much lower insulin requirement in the first several years after diagnosis , rare microvascular complications , and rare presence of diabetes antibodies . patients with ws show smaller glycemic variability than individuals with type 1 diabetes mellitus , and this may be associated with persistent residual insulin secretion . a loss of vasopressin - producing neurons in the hypothalamus has been well documented in this disease and is thought to be the cause of ws - associated diabetes insipidus.17 , 18 neuroradiologists have reported a loss of signal intensity in the posterior pituitary , indicating an absence or degeneration of the neurohypophysis18 , 19 ; some patients have been found to have  empty sella  . patients with ws demonstrate progressive ophthalmologic symptoms that usually occur after diabetes mellitus . besides optic atrophy , constriction of visual fields and declined visual acuity and color vision are the other ophthalmological findings in ws ; however , diabetic retinopathy is rarely observed . al - till et  al performed a study to investigate ophthalmologic abnormalities in fifteen patients with ws . of 15 patients with ws reviewed in this study , 93.3% had optic atrophy , 92.9% had color deficit , 66.6% had cataract , 30% had pigmentary retinopathy , and 20% had diabetic retinopathy . the ophthalmic signs were a progressive decrease in visual acuity , constriction of the peripheral visual field with or without central scotoma , color vision disturbances , and bilateral optic disc atrophy . recently , the retinal thinning has been proposed as a marker of disease progression in patients with ws . deafness in ws is commonly a high - frequency , symmetric , sensorineural hearing loss , usually manifesting in the second or third decade with a relatively slow rate of deterioration.26 , 27 some studies have reported urinary tract abnormalities ( hydroureter , urinary incontinence , recurrent infections ) in patients with ws , that these abnormalities are expected in about 66% of patients . urinary tract abnormalities include obstruction of the ureters , an atonic bladder with a large capacity , high pressure bladder with sphincteric dyssynergia , and incontinence . urinary tract dilatation is presented in 45% of patients with ws , which may be secondary to chronic high urine flow rate or neurodegeneration in different levels of the urinary tract . differential diagnosis of ws includes : ( 1 ) mitochondrial disorders : maternally inherited diabetes mellitus and deafness , leber hereditary optic neuropathy ; ( 2 ) thiamine - responsive megaloblastic anemia , diabetes , and deafness ; ( 3 ) autosomal dominant optic atrophy ; ( 4 ) x - linked charcot - marie - tooth disease type 5 ; ( 5 ) deafness , dystonia , optic neuronopathy syndrome ; ( 6 ) friedreich ataxia ; ( 7 ) bardet - biedl syndrome ; ( 8) alstrom syndrome ; and ( 9 ) congenital rubella syndrome . the association of diabetes mellitus with optic atrophy also occurs in friedreich 's ataxia , refsum disease , alstrom syndrome , lawrence - moon syndrome , kearn - sayre syndrome , and deafness and diabetes in the3243  mitochondrial dna mutation . the pathogenesis of the disease remains unknown , but genetic linkage studies have shown that the mutations of the wfs1 gene are responsible for the symptoms in 90% of cases meeting specific wfs diagnostic criteria . the wfs1 gene encodes an 890-amino - acid protein called wolframin , a putative multispanning membrane glycoprotein of the endoplasmic reticulum . although no function has yet been ascribed to wolframin ; however , its localization to the endoplasmic reticulum suggests it can play a role in calcium homeostasis , membrane trafficking and protein processing . there is currently no cure for ws , but there are treatments for some of the features . diabetes mellitus is treated with insulin , and diabetes insipidus with vasopressin . while hearing aids can help with hearing loss , there is unfortunately no treatment for vision loss . renal problems may be treated by catheterization ( passing a thin , flexible tube into the bladder to drain away urine ) , and some of the neurological symptoms can be treated with medication . based on the findings of the present case , it is highly recommended that , in patients with diabetes mellitus who have optimal blood sugar presenting with polyuria and polydipsia , we need to do urine specific gravity to prove the presence of diabetes insipidus . in such patients , performing an ophthalmologic evaluation can probably reveal this rare disorder of wolfram syndrome . in addition , ophthalmologists should be aware that in patients presenting with diabetes mellitus and optic atrophy without any signs of diabetic retinopathy , it is necessary to perform a hearing test as well as collect and analyze 24-h urine output . thus , awareness of this condition and timely diagnosis is important for improving patient prognosis , anticipating associated complications , and enabling timely genetic counseling for family members .