|Year : 2015 | Volume
| Issue : 1 | Page : 33-37
A rare case of Wolfram syndrome
Anubhav Chauhan1, Shashi Datt Sharma1, Ranesh Kumar2
1 Department of Ophthalmology, Regional Hospital Hamirpur, Hamirpur, India
2 Department of Surgery, Zonal Hospital Mandi, Mandi, Himachal Pradesh, India
|Date of Web Publication||29-Mar-2016|
Pine Castle, Near Mist Chamber, Khalini, Shimla - 171 002, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
A 19-year-old male with type 1 diabetes mellitus and juvenile rheumatoid arthritis (JRA) presented to a secondary care institute with painless, progressive diminution of vision. Ocular examination revealed bilateral optic atrophy. A suspicion of Wolfram syndrome (WFS) led to a battery of investigations for known association of many entities with this syndrome. Positive associations with this syndrome such as short stature, hydronephrosis, seizures, and color vision deficiency were present in our case. To the best of our knowledge and after undergoing extensive literature search on the internet, this is probably the first reported case of WFS with JRA and without diabetes insipidus as a whole.
Keywords: Diabetes mellitus, optic atrophy, Wolfram
|How to cite this article:|
Chauhan A, Sharma SD, Kumar R. A rare case of Wolfram syndrome. Egypt Retina J 2015;3:33-7
| Introduction|| |
Wolfram syndrome (WFS) is a rare neurodegenerative disorder characterized by diabetes insipidus (DI), diabetes mellitus, optic atrophy, deafness, and a wide variety of central nervous system abnormalities. Insulin-dependent diabetes mellitus (IDDM) with optic atrophy is sufficient criteria for the diagnosis.  WFS is caused by biallelic mutations of the WFS1 gene encoding wolframin, a transmembrane glycoprotein that localizes in the endoplasmic reticulum (ER). Loss of WFS1 function is thought to result in chronic ER stress-mediated apoptosis of pancreatic B-cells, neuroendocrine, and neuronal cells leading to a progressive decline of endocrine function and neurodegeneration.  Here, we report a very rare case of WFS.
| Case Report|| |
A 19-year-old male [Figure 1] presented to a secondary care institute of the hilly state with a history of painless, progressive loss of vision in bilateral eyes for the past 3 years. He stated that though he has been prescribed glasses from some local spectacle makers 3 years back, his vision is not clear, and is deteriorating. He gave a history of being a patient of IDDM since the age of 5 years and juvenile rheumatoid arthritis (JRA) (deformed hands) [Figure 2] and showed his old treatment records. There was no history of any consultation with an ophthalmologist during the past 15 years. There was a positive history of polyuria (3-4 L/day), nocturia and antiepileptic drug (carbamazepine) intake for past 3 years His developmental history, prenatal, perinatal, and postnatal histories were all unremarkable but family history revealed that his brother also had diabetes mellitus-type 1. There was no other significant personal and family history.
On examination, his speech, intelligence, language, and hearing were within normal limits. General physical examination was carried out and the positive findings were a height of 4 feet 7 inches and weight of 35 kg with deformed hands. Examination of gonads was within normal limits. His visual acuity was 5/60 in both the eyes, and there was an improvement to 6/60 in the right eye with −1.50 D sphere/−0.50 cylinder at 120° and 6/60 with −1.50 D sphere in the left eye. The visual axis was normal, pupils were semi-dilated and not responding to light, ocular movements, slit lamp examination, intraocular pressure, and gonioscopy were normal. Color vision tests using Ishihara charts revealed red-green color deficiency. Fundus examination with direct ophthalmoscopy revealed bilateral optic atrophy [Figure 3] and [Figure 4] without any diabetic retinopathy changes. Based on the above findings of type 1 diabetes mellitus with bilateral optic atrophy, a diagnosis of WFS was made. Knowing the association of this syndrome with many entities, a complete hematological examination which included complete hemogram with erythrocyte sedimentation rate, blood sugar, glycosylated hemoglobin, renal and liver function tests, serum electrolytes, serum osmolality, Vitamin D levels, and hormonal levels were carried out which revealed a raised blood glucose as the only positive finding while complete urine analysis (including osmolality) was within normal limits. Water deprivation tests did not yield any positive results. He had a normal audiometric test. Electrocardiography was normal. Genetic analysis could not be performed due absence/lack of facility of carrying out these tests in this hilly terrain.
He was advised magnetic resonance imaging (MRI) brain, gastrointestinal endoscopy, perimetry, and surgical/urological consultation taking into consideration the various associations with this syndrome and was told to attend a tertiary care consultation (as the above facilities were not available at the secondary care institute) and review back to us. The patient reviewed back to us after 2 weeks, and the positive findings were, MRI brain showed pontomedullary atrophy with bilateral optic atrophy [Figure 5],[Figure 6],[Figure 7] and [Figure 8], intravenous pyelography revealed bilateral Grade 1 hydronephrosis with short infundibulum bilaterally with bilateral hydroureter with over distended urinary bladder with significant postvidal residual urine. There were no gastrointestinal ulcers. His visual fields demonstrated generalized constriction [Figure 9],[Figure 10],[Figure 11] and [Figure 12]. He was advised regular follow-up from the concerned specialties, and we advised him to get his brother examined as well.
| Discussion/Comments|| |
It was first described in 1938, as four siblings with diabetes mellitus and optic atrophy were first reported by Wolfram.  WFS is a rare (1/770,000) autosomal recessive genetic disease.  The patients present with nonautoimmune and nonhuman leukocyte antigen linked diabetes mellitus associated with optic atrophy in the first decade; DI and sensorineural deafness in the second decade; renal tract abnormalities early in the third decade; and multiple neurological abnormalities such as cerebellar ataxia, myoclonus, and psychiatric illness early in the fourth decade. Diabetic retinopathy is rarely observed in these patients.  Besides optic atrophy, decline visual acuity, and color vision are the other ophthalmological findings in WFS.  In our case IDDM, optic atrophy, JRA, color vision deficiency, and hydronephrosis were present without diabetic retinopathy changes while DI and sensorineural hearing loss was absent.
Hearing loss, mainly in high frequencies, may be present in 48% of patients and DI of hypothalamic origin may occur in the third decade of life in up to 75% of cases. Dilation of the urinary tract is observed in 45% of cases which may be secondary to chronic high urine flow rates or neuronal degeneration at various levels of the urinary tract. Atony of the bladder and the whole urinary tract may also be observed.  Our patient Intravenous Pyelography revealed bilateral Grade 1 hydronephrosis with short infundibulum bilaterally with bilateral hydroureter with overdistended urinary bladder with significant postvidal residual urine.
Other abnormalities include an absent gag reflex, cold intolerance, loss of taste or smell, autonomic neuropathy, cerebellar dysarthria, seizures  along with spinocerebellar degeneration, delayed sexual maturation, a small sella tursica, male hypogonadism due to primary gonadal failure,  hypothyroidism and growth failure.  Growth failure and seizures was present in our patient as well.
Psychiatric disorders associated with Williams syndrome (WS) include severe depression and impulsive, aggressive behavior. There are two types of WS with many overlapping features. In addition to the usual features of WS, individuals with WS type 2 have stomach or intestinal ulcers and excessive bleeding after an injury. People with WS type 2 do not develop DI.  Our patient did not have DI and so could be a part of WS2 but at the same time did not have stomach or intestinal ulcers.
The MRI highlights of brain atrophy images, in particular, pontic and mesencephalic. The most common causes of mortality and morbidity are due to the neuropsychiatric symptoms and to the urologic complications. The average age of the death is from 30 to 35 years on average.  Our patient MRI brain showed pontomedullary atrophy. These patients need close follow-up. A high degree of suspicion on the part of the ophthalmologist is required in clinching the diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We would like to thank our patient.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ari S, Keklíkçí U, Caça I, Unlü K, Kayabasi H. Wolfram syndrome : c0 ase report and review of the literature. Ann Ophthalmol (Skokie) 2007;39:53-5.
Rohayem J, Ehlers C, Wiedemann B, Holl R, Oexle K, Kordonouri O, et al. Diabetes and neurodegeneration in Wolfram syndrome : a0 multicenter study of phenotype and genotype. Diabetes Care 2011;34:1503-10.
Kwon BS, Han SH, Lee SA. The presence of periodic limb movement disorder in a patient with diabetes mellitus and optic atrophy (Wolfram Syndrome). Sleep Med Res 2014;5:67-71.
Diyane K, Mghari GE, Ansari NE. Wolfram syndrome: Report of two new cases. J Endocrinol Diabetes Mellitus 2014;2:122-4.
Manaviat MR, Rashidi M, Mohammadi SM. Wolfram syndrome presenting with optic atrophy and diabetes mellitus : t0 wo case reports. Cases J 2009;2:9355.
Naderian G, Ashtari F, Nouri-Mahdavi K, Sajjadi V. A case of Wolfram syndrome. J Ophthalmic Vis Res 2010;5:53-6.
Buryk MA, Bangalore-Krishna K, Rivera-Vega M, Garibaldi L. Wolfram syndrome: Are we aware of the severe hypoglycemic unawareness? J Diabetes Res Clin Metab 2013;2:4.
Moghtaderi M, Asadi F, Gorji M, Allahverdi B, Sayarifard F, Rostami P. A rare case of Wolfram syndrome. J Pediatr Nephrol 2015;3:35-7.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]