| Abstract|| |
We present an autopsy case of a 19 year old male admitted for breathlessness and oliguria. He was diabetic since 7 years of age and was on insulin. Patient was on testosterone and anti hypertensives. He was diagnosed of hypocontractile bladder and congenital bilateral megaureter with vesico-ureteric reflux 2 years back. History of hemiparesis 2 years back. CT scan of the brain showed a right fronto- parietal healed infarct. At autopsy, bilateral kidneys showed coarse granularity and scarring. Pelvicalyceal system and both ureters were dilated. A right sided intrabdominal testes was identified. On histology, kidney showed features of diabetic nephropathy and pancreas showed decreased number of islet cells. Correlating the clinical, laboratory and autopsy parameters, our case satisfies the EURO-WABB criteria (1major+2minor) for diagnosis of Wolfram Syndrome, even though genetic confirmation could not be done.,
Keywords: Autopsy, DIDMOAD, Wolfram syndrome
|How to cite this article:|
Padmanabhan A, Parihar A, C. Vartak US, Gadgil NM. Wolfram syndrome: A rare case report. Indian J Pathol Microbiol 2019;62:477-80
| Introduction|| |
Wolfram syndrome is a rare autosomal recessive diffuse neurodegenerative disorder with a prevalence of 1 in 7,70,000 and features including diabetes mellitus (87%), diabetes insipidus (42%), optic atrophy (7%), and deafness (48%), with genito-urinary, endocrine, and central nervous system abnormalities. It is also called as DIDMOAD.
Genetics involve mutation in WFS1 gene, coding for Wolframin protein involved in neurons and pancreatic beta cell metabolism.
It was first described in 1938 by Wolfram et al. in eight siblings from a family, who developed diabetes mellitus, optic atrophy, and subsequently sensorineural deafness and neurogenic bladder.
| Case history|| |
A 19-year-old male diagnosed with a case of type 1 diabetes mellitus with hypogonadism with congenital bilateral megaureter with hypocontractile bladder. He was on insulin since 7 years of age. He complained of repeated urinary tract infection and was diagnosed with bilateral Vesico-ureteric reflu × 2 years back for which DJ stenting was done. He also had a history of left hemiparesis and one episode of generalized tonic clonic seizures with slurring of speech 2 years back and was started on antiepileptics. He lacked secondary sexual characters and was on testosterone since 2 years. He was born out of nonconsanguineous marriage and his younger brother and first male cousin had similar complains. He was admitted with complains of breathlessness, oliguria, and had facial puffiness for last 3 months.
On external examination, pallor and edema was present. BP was 180/100 mm Hg. Hematological investigations showed features of Iron deficiency anemia. BUN and serum creatinine were elevated with subnormal hormonal (LH, FSH, Testosterone) level. Blood sugar levels pointed to a diabetic state (196 mg%). Fundus examination showed no evidence of papilledema, retinopathy, or optic atrophy. Abdomen USG revealed bilateral hydronephrosis with hydroureters. Computed tomography findings of brain showed a chronic infarct in right high frontoparietal region.
Patient expired after a ward stay of 48 hours and autopsy was performed. On external examination, patient was short statured with lack of secondary sexual characters, empty scrotal sacs, and hypospadias.
At autopsy, brain showed a slight depression at the right frontoparietal region, at the site of infarct [Figure 1]. Bilateral kidneys showed coarse granularity with broad U-shaped scars on the surface and altered corticomedullary ratio [Figure 2]. Pelvicalyceal system was dilated along with bilateral ureters measuring 1.2 cm in diameter throughout [Figure 3]. Right testes (2 × 3 × 1 cm) was identified in the inguinal region with mesenteric attachment 15–18 cm from ileocecal junction [Figure 4]. Cut section showed homogenous gray-white appearance.
|Figure 1: Slight depression at right high parietal, right front-oparietal region, at the site of infarct|
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|Figure 2: Bilateral kidneys show coarse granularity on the cortical surface with broad U-shaped scars on the external surface. Corticomedullary ratio is not maintained. Pelvicalyceal sysytem is dilated and distorted|
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|Figure 3: Bilateral ureters showing dilation throughout with diameter of 1.2 cm|
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|Figure 4: Right testes (2 × 3 cm) in the inguinal region with mesenteric attachment of 15–18 cm from the ileo-cecal junction|
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Histopathology of kidneys showed lesions of diabetic nephropathy [Figure 5]. Ureteral lining showed flattening of transitional epithelium [Figure 6]. Brain showed white matter edema with gliosis at right frontoparietal infarct [Figure 7]. Decreased population of islet cells noticed in pancreas [Figure 8]. Testis showed spermatogonia with interstitial fibrosis. [Figure 9]. Lung sections showed pulmonary edema. The final cause of death reported was renal failure in a case of diabetes and hypertension with healed cerebral infarct and megaureter (suspected Wolfram Syndrome), however, needs genetic workup or confirmation.
|Figure 5: Glomeruli are sclerosed (KW lesion) with thyroidisation of tubules and interstitial inflammation. There is thickening of arterioles (onion skin peel appearance)|
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|Figure 8: Pancreas showing decreased population of islet cells with normal acini|
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|Figure 9: Testes showing only spermatogonia with increased interstitial fibrosis suggestive of atrophic testes|
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| Discussion|| |
Wolfram syndrome is a progressive neurodegenerative disorder presenting with non-HLA-linked diabetes mellitus along with optic atrophy in the first decade, diabetes insipidus and sensorineural deafness in the second decade, and renal tract abnormalities early in the third decade of life. Multiple neurological abnormalities, such as myoclonus, cerebellar ataxia, and psychiatric illness, appear during fourth decade in 60% of the patients. Wolfram patients usually die from central respiratory failure as a result of brain stem atrophy in the third or fourth decade of life.
Pathophysiology suggests that Wolframin is involved in the survival pathways of neurons and pancreatic beta cells.
The diagnosis of Wolfram syndrome in our patient was based on clinical, laboratory investigations, gross, and microscopy evaluation of all organs at autopsy. Even though genetic study could not be done, our case satisfies the Euro-WABB criteria (one major + two minor) [Table 1] for the diagnosis of Wolfram syndrome.,
Diabetes mellitus is seen in 87% of patients and the mean age of onset is 6–15 years. The cause is selective nonautoimmune linked, beta cell death. Multiple sections studied from the entire length of pancreas revealed educed number of islets. Acini were unremarkable.
There was no history of visual disturbances/hearing impairment in our patient and audiometry was not performed. The median age for diagnosis of optic atrophy is around 11 years. Sensorineural deafness generally manifests in around 48% patients in the second to third decade. The cause of blindness is severe axonal loss and demyelination of optic nerve, chiasma, and tracts. Deafness is due to degenerative atrophy of vestibulocochlear nuclei, auditory nerve, and pathways.
Dilatation of urinary tracts is observed in 45%–65% patients. It may be secondary to chronic high urine flow rates or neuronal degeneration at various levels of urinary tract. Tekgul et al. studied urinary tract in 14 patients with WS and observed that upper tract dilatation was present in 11/14 cases. Urodynamic showed that 7/14 had low capacity bladder and 6 patients had atonic bladder, and 1 normal bladder.
Delayed sexual maturation and male hypogonadism due to primary gonadal failure have been reported in 6% of male patients. Our patient had unilateral undescended testes. This feature has not been reported previously.
Neurological signs, such as ataxia, epilepsy, and cognitive impairment are seen in 29% of patients. Our patient had history of hemiparesis and one episode of generalized tonic clonic convulsions. Gliosis was observed at temperoparietal region. Brain stem section did not show any degenerative changes. Our patient was 19-year-old with a developmental age of 10 years.
Family history was positive in his younger brother and one male cousin.
Death in WS is premature and is due to intercurrent infection, respiratory failure due to brain stem atrophy. Our patient died of acute renal failure and pulmonary edema.
Out of the 11 cases of Wolfram syndrome reported in literature from India, this is the first autopsy case.,,
| Conclusion|| |
Cases of juvenile diabetes mellitus with associated visual disturbances, deafness, polyuria, and neurological symptoms have to be investigated systematically to rule out Wolfram syndrome. Awareness and timely multidisciplinary workup and diagnosis is important for monitoring the patient for further complications and genetic counselling of family members.
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.
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Conflicts of interest
There are no conflicts of interest.
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