Year : 2000 | Volume
: 11 | Issue : 1 | Page : 53--58
Wolfram's (DIDMOAD) Syndrome and Chronic Renal Failure
Mojaly Ahmed Hasan, Issa Hazza, Abdulhamid Najada
Pediatric Unit, King Hussein Medical Center, Amman, Jordan
Mojaly Ahmed Hasan
Pediatric Consultant, King Hussein Medical Center, P.O. Box 6080, El-Zarqa
Wolfram«SQ»s syndrome is usually considered as an autosomal recessive condition, with wide phenotypic variation. The syndrome is commonly called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness), although some patients have additional clinical findings including ataxia, hypogonadism, hydronephrosis and psychiatric illnesses. We report a patient with DIDMOAD syndrome with emphasis on the urological tract and its progressive complications. Unfortunately, he developed end-stage renal failure and needed hemodialysis at the age of 14 years. The presentation, investigations and management are discussed.
|How to cite this article:|
Hasan MA, Hazza I, Najada A. Wolfram's (DIDMOAD) Syndrome and Chronic Renal Failure.Saudi J Kidney Dis Transpl 2000;11:53-58
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Hasan MA, Hazza I, Najada A. Wolfram's (DIDMOAD) Syndrome and Chronic Renal Failure. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2020 Jul 15 ];11:53-58
Available from: http://www.sjkdt.org/text.asp?2000/11/1/53/36694
In 1938, Wolfram et al, at the Mayo clinic described a family of eight siblings of whom four had diabetes mellitus and optic atrophy. Of these, three subsequently developed sensorineural hearing loss and two of the three developed neurogenic bladder-paresis. The syndrome was called after Wolfram.  An alternative acronym of DIDMOADUD has been proposed since urological alterations can bring about serious sequels in these individuals. 
The syndrome is inherited as a somatic recessive disease with varying expression. It may be sporadic, although it has been proven that some cases of DIDMOAD syndrome may result from mutation in the mitochondria genome. 
The prevalence of Wolfram's syndrome is unknown but an estimate of one in 100,000 based on frequency of 1:150 juvenile diabetics referred to a diabetes clinic is undoubtedly too high.  The estimated prevalence-rate of one in 770,000 in the UK study, where a physician might see one or two patients in his or her working life time may be more realistic.  Although there is a high prevalence of consanguineous marriages in the Middle East and the North African region, only few cases of Wolfram's syndrome have been reported from these regions. It may be reasonable to assume that Wolfram's syndrome is underreported from this part of the world.
The following case report is of a child who unfortunately developed end-stage renal disease (ESRD) and needed hemodialysis.
A 15-year-old boy who was born to consanguineous Jordanian parents at full term with uneventful pregnancy and delivery. His birth weight was 3.5kg. The patient is the third of ten siblings, seven boys and three girls. An older sister had died of diabetes mellitus at the age of 11 years. The father died in a building construction accident several years before. Neither the parents nor the living siblings had clinical features of DIDMOAD syndrome.
At age of nine years the patient developed polyuria, polydepsia, polyphagia and weight loss. He had hyperglycemia and primary type I diabetes mellitus was confirmed by excluding any precipitating cause. The patient was started on Intermediate acting Insulin 0.7 IU /kg/day divided in two doses. The blood glucose was well controlled for the next six years.
Two years later, at age of 11, the patient started to complain of dysuria, fever, chills and nocturia. Urine culture grew E. Coli of >10 5 /ml. Serum creatinine was 200 µmol/L and serum urea was 15mmol/L. Abdominal ultrasonography revealed dilated right pelvicalyceal system and small left kidney. Intravenous urography revealed a moderately dilated right kidney and nonfunctioning small left one.
Radionuclide scan by DMSA 99mTc revealed a small left kidney with poor tracer uptake. The right kidney had moderately reduced tracer uptake with irregular contour. Split renal function showed that the left renal glomerular filtration rate (GFR) was 25% whereas the right renal GFR was 75%.
Micturating cystourethrography showed a smooth wall of the urinary bladder with bilateral vesico-ureteric reflux reaching to both pelvi-calyceal systems causing severe dilatation of the right kidney and both ureters (grade 5). The urethra appeared normal [Figure 1]. The patient urinated on request but could not empty his bladder completely. Urodynamic study showed free flow of 15ml/ sec. Post-voiding residual volume was 150ml.
Cystourethroscopy showed no urethral stricture but atonic bladder. The diagnosis of neurogenic low-pressure bladder was thus confirmed.
The Patient was prescribed prophylactic antibiotics and trained for clean intermittent catheterization. He was not compliant in part due to the poor socioeconomic condition of the family. The patient was hospitalized several times a year with clinical features of urinary tract infection. During the hospitalizations, the patient was motivated and his compliance and renal function were re-evaluated. However, at the age of 13 years he developed moderately severe chronic renal failure. One year later, he needed hemodialysis twice weekly for reaching end-stage renal disease.
At age of 12 years, the patient was noticed to have a hearing loss. An audiogram was done and proved the presence of bilateral high tone sensorineural hearing loss. We considered DIDMOAD syndrome and ophthalmic consultation revealed bilateral optic atrophy [Figure 2].
At the age of 13 years, the patient had upper gastrointestinal bleeding. Endoscopy revealed a duodenal ulcer for which he was managed conservatively with satisfactory results.
Patient's height and weight were just below the 3rd centile, mid parental height was at 75%. He was pre pubertal, which proved to be primary hypogonadism with high basal LH and FSH. The patient had normal sense of smell, but his gait was ataxic and both knee and ankle jerks were sluggish. The cranial magnetic resonance image (MRI) was abnormal, [Figure 3]. It showed generalized brain atrophy, and a pituitary gland that was small in size for the patient's age. The high signal intensity of the posterior pituitary gland was absent, however, there was no intra or supra sellar mass lesion. The patient is still on Intermediate Insulin therapy and attending regular school with good performance. Water deprivation test could not be done for his chronic renal failure.
The association of diabetes mellitus and optic atrophy originally characterized Wolfram's syndrome. Our patient fulfilled the requirements for Wolfram's syndrome in that he had all the findings mentioned in the acronym of DIDMOAD. The incidence of clinical features with their mean age of presentation was reviewed by Barrett et al in a United Kingdom nationwide study of Wolfram syndrome of 45 cases; 29 index patients and 16 secondary patients (all siblings) [Table 1]. 
Dilatation of the urinary tract was reported in 15% of 88 cases reviewed by Cremers et al  The incidence of the dilatation of the urinary tract in DIDMOAD syndrome is usually underestimated, since it is usually asymptomatic and patients are not investigated until they have some symptoms related to their urinary tract other than polyuria and polydepsia which are usually ascribed to insulin dependent diabetes mellitus (IDDM).
Thanos et al  reported three cases of Wolfram's syndrome with dilatation of the urinary tract, which was considered in two of them to be either a consequence of high diuresis associated with diabetes insipidus or a degenerative process affecting the central and peri-pheral nervous system. Their third case, however, had severe bilateral hydronephrosis without diabetes insipidus or urinary outlet obstruction.
In contrast, Aboseif et al  reported two cases of Wolfram's syndrome with hyperreflexive neurogenic bladder with sphincter dyssynergia, which resulted in severe urinary dilatation. One patient was managed conservatively with clean intermittent catheterization and anticholinergic medication and the second patient underwent several attempts of surgical correction. Penden et al  reported five patients who had evidence of urinary tract dilation similar to our patient.
The cause of urinary tract dilatation in this syndrome is unclear. It is unlikely to be due to diabetic peripheral neuropathy because of the short duration of diabetes. The dilatation is most likely due to a primary degeneration of the enervation of the urinary passages, which is further aggravated by the diabetes insipidus.. In addition, the clinical syndrome suggests a progressive degeneration involving other parts of the nervous system. These include the second and the eighth cranial nerves; the supra optic and para-ventricular nuclei; and part of the cerebellum.
Swift et al,  reviewed 68 Wolfram's syndrome patients with age range from eight to 43 years; 41 (60%) of them had psychiatric illness with very severe symptoms in 25%, manifesting as psychosis, impulsive verbal and physical aggression and suicidal attempts.
Unfortunately, our patient presented with impaired kidney function and was poorly motivated. So he failed to benefit from the regimen of clean intermittent catheterization to relieve the upper urinary tract dilatation. Urinary diversion might have been a better approach in this patient.
His renal failure might not have been all due to obstructive uropathy. It is well known that diabetic nephropathy is the most prevalent cause of ESRD in adults, accounting for over 25% of patients receiving long-term hemodialysis. The three-year survival rate for patients with IDDM and ESRD with dialysis has only recently improved from 30% to 60%.  The diabetic patients with DIDMOAD syndrome who have dilatation of the urinary tract and urinary tract infections, will have increased morbidity and mortality compared with other diabetic patients with intact urinary tract.
Despite the multi-system disease our patient could attend two sessions of hemodialysis weekly as well as regular school with good academic achievement.
Other features seen in this patient, which have been reported in the literature are ataxia  and delay in sexual development. 
Due to the high rate of consanguineous marriage in the Middle East and North Africa, we would suggest to examine and investigate children with IDDM for any associated anomaly of DIDMOAD, mainly the urinary tract dilatation.
We conclude that in Wolfram's syndrome, urinary tract dilatation may be present at an early age and is a major cause of morbidity and mortality in this syndrome. Careful monitoring of all IDDM patients for other signs of the syndrome may be warranted.
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