Postgraduate Medical Journal (1986) 62, 859-863

DIDMOAD syndrome with megacystis and megaureter

P. Chu', W.G. Staff2, J.A. Morris3 and J.M. Polak4'Department ofMedicine, Royal Lancaster Infirmary, Lancaster, 2Department of Urology, Royal LancasterInfirmary, Lancaster, 3Department ofPathology, Lancaster Moor Hospital, Lancaster LAI 3JR, and4DepartmentofHistochemistry, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12OHS, UK.

Summary: A case ofDIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy andnerve deafness) is described. There was unusually severe urinary tract dilatation which led to an ilealconduit diversion. Immunohistological study of the bladder wail and ureter revealed a marked diminutionin nerve fibres, which may have been primary or secondary to the muscle hypertrophy. The possiblepathogenesis of the urinary tract dilatation is discussed in relation to this finding.

Introduction

The DIDMOAD syndrome is a rare familial diseasecharacterized by diabetes insipidus, diabetes mellitus,optic atrophy and nerve deafness. The association ofdiabetes mellitus and optic atrophy was first describedas a familial event by Wolfram (1938) and thesyndrome has been reviewed by Rose et al. (1966),Page et al. (1976) and Cremers et al. (1977). It isthought to be due to a single recessive gene althoughthe pathogenesis is unknown. A common componentofthe syndrome is urinary tract dilatation which variesfrom mild hydronephrosis to megaureter andmegacystis (Raiti et al., 1963; Bretz et al., 1970;Moore, 1971; Marquardt & Loriaux, 1974; Page et al.,1976; Aragona et al., 1983). The most frequentlyproferred explanation for the urinary tract dilatationis that high urine flow due to diabetes insipidus causespassive dilatation. However, we report a case ofDIDMOAD syndrome with megacystis andmegaureter in which immunohistological studies ofthe bladder wall and ureter demonstrated a markeddiminution in nerve fibres. This might be of path-ogenic significance.

Case report

The patient developed insulin-dependent diabetesmellitus at 8 years of age. There was no history of thiscondition in his immediate family which includedthree male siblings. At age 12 years he complained ofblurred vision and was found to have impaired visual

acuity (6/12 both eyes, uncorrectable) and bilateraloptic atrophy. There was no evidence of diabeticretinopathy. He remained relatively well in his teenswith normal schooling and growth, apart from hy-poglycaemic attacks. He first presented to theUrological Department at 23 years of age. His maincomplaint was lack of urinary control which hadoccurred regularly each night during sleep for theprevious 9 months, and which also occurred if hedozed during the day. He was also aware of extremethirst and had observed that he was producing a largeamount of urine daily, in spite of the fact that hisdiabetes mellitus was under satisfactory control. Hewas apparently experiencing normal bladder sensationand said that he was achieving normal erectionsalthough ejaculation was infrequent. Physical examin-ation revealed that his bladder was distended beyondthe umbilicus. Apart from optic atrophy (visualacuity 6/24 on the right and 6/36 on the left withglasses) there was no other detectable abnormality ofthe central nervous system. There was no evidence ofperipheral neuropathy or of orthostatic hypotension.

Initial urological investigations included an in-travenous urogram (Figure 1). This showed grossupper tract dilatation in association with the largebladder. At that time his blood urea was 7.2 mmol/litreand serum creatinine 130 JAmol/litre. His urine wassterile and remained so throughout subsequent inves-tigations and treatment. No reflux was demonstratedon a micturating cystogram. A uretherogram showednormal anatomical features of the posterior urethra(Figure 2). A cystometrogram performed without apreliminary drainage of the bladder showed a rapidrise in pressure leading to detrusor contractionsassociated with an apparently normal desire to void.

t The Fellowship of Postgraduate Medicine, 1986

Correspondence: J.A. Morris, M.A., M.B., B.Chir.,M.R.C.Path.Accepted: 20 February 1986

Protected by copyright.

on Novem

ber 29, 2020 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.62.731.859 on 1 Septem

ber 1986. Dow

nloaded from

860 CLINICAL REPORTS

i; j ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..........:.::.

o.>

.:...:..........

Nt00t§SiS 00i....U...... .:._ | l| !E l ~~~~~~~~........

EIlIIEi. ...,.2S~

Figure 1 Intravenous urogram 60 minutes (post mic-turition) showing gross upper tract dilatation and a largeresidual urine

Flow rates were normal. During a period of waterdeprivation he produced approximately 300 ml urineper hour with a concentration between 176 and193 mosmol/kg. In this period his serum concentrationrose from 289 to 306 mosmol/kg. After an intramus-cular injection of 2 tig of desmopressin his urine flowrate fell to 220 ml/hour and the maximum concentra-tion achieved was 280 mosmol/kg. These results wereconsistent with nephrogenic diabetes insipidus, alth-ough there was a possible slight response to vasopres-sin and a concomitant neurogenic diabetes insipiduscould not be excluded. There was no subjectivehearing deficit but audiometry revealed high tonenerve deafness.

Treatment with desmopressin and chlorpropamidejointly and separately were tried but there was noevidence ofany diminished urinary output and in spiteof regular bladder emptying his main problem ofurinary incontinence persisted. A bladder neck in-cision was performed followed by a period of catheterdrainage. His urine output continued at a high levelbut his blood urea and creatinine fell from theimmediate pre-operative level of 10.6 mmol/litre and153 pmol/litre, respectively, to 7.1 mmol/litre and121 JAmol/litre post-operatively whilst on catheter

i.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ .......

Figure 2 Voiding urethrogram Showing normal blad-der neck and posterior urethra.

drainage. Isotope renography performed post-operatively, whilst still on catheter drainage, showed asignificant improvement from the pre-operative state.However, after removal of his catheter his blood ureaand creatinine rose to 8.9 mmol/litre and 158 pmol/litre respectively and his condition returned to itsformer state.A uinary diversion was considered A major obsta-

cle to this was the vast amount ofurine being producedwhich might swamp the appliancer Although whilst oncatheter drainage the patient s general condition andrenal function as judged by blood urea creatinine andrenography had improved there had been little fall inucne output However it was thought that improveddrainage might improve the nephrogenic componentof his diabetes insipidus. Thus, 10 months afterpresentation the patient was submitted to ileal conduitdiversion. Permission for a full thickness biopsy of the

Protected by copyright.

on Novem

ber 29, 2020 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.62.731.859 on 1 Septem

ber 1986. Dow

nloaded from

CLINICAL REPORTS 861

bladder was obtained and this together with specimensof both ureters, appendix and off-cuts of ileum weresent for histological examination.The patient made an uneventful recovery. At the

time of discharge his urine output had fallen tobetween 3700 and 4500 ml/day, and his blood urea to5.1 mmol/litre and creatinine to 122 jumol/litre. Apost-operative intravenous urogram showed satisfac-tory resolution ofthe upper tract distension (Figure 3).A subsequent water deprivation test revealed a contin-uing inability to concentrate the urine beyond200 mosmol/kg, but following intramuscularvasopressin the urine reached a maximum concentra-tion of 320 mosmol/kg. These results are difficult tointerpret but the simplest explanation is that there wasboth nephrogenic and neurogenic diabetes insipidusand that the former component had improved follow-ing the drainage procedure.

Three years post-operatively he was working fulltime. He had normal renal function and his daily urineoutput averaged 5900 ml. He had decided to take nomedical treatment other than that for his diabetesmellitus as he felt it unnecessary.[ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~...... .

^ .......... . ---- o, ............... . .~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....

1 | .S ^ .~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~A...... .... ... g

Figure 3 Intravenous urogram following ileal conduitdiversion. Upper tract dilatation persists but is considera-bly improved compared with the pre-operative state.

Histopathology

Sections of the bladder and ureters showed markedthickening of the wall due to muscular hypertrophyand fibrosis. There was submucosal oedema with mildinflammation and moderate hyperplasia of the tran-sitional epithelial lining. The appendix and smallintestine were morphologically normal.

Immunohistological staining was performed oncryostat sections of snap-frozen formalin-fixedmaterial. A conventional immunoperoxidase bridgetechnique (Sternberger, 1979) was used with optimaldilutions of primary antisera and a full range ofpositive, negative and blocking controls as detailedelsewhere (Gu et al., 1985). Primary antisera reactiveagainst the following were used; dopamine-p-hydrox-ylase (DBH, a marker for catecholaminergic nerves),neurone-specific enolase (NSE, a general neuralmarker), S-100 (a protein present in glial cells), theamine serotonin (5-HT) and the peptides somatos-tatin, neuropeptide Y (NPY), vasoactive intestinalpeptide (VIP) and peptide histidine isoleucidine (PHI).There was gross depletion of nerves in bladder andureters with immunostaining varying from nil tominimal. By contrast, in the appendix and smallintestine, apart from a reduction in VIP, the stainingappeared normal.

Discussion

This patient had diabetes mellitus, diabetes insipidus,optic atrophy and high tone nerve deafness and thusfulfills the criteria for the DIDMOAD syndrome.However, there was no family history. The precisecause of diabetes insipidus in this condition is some-what uncertain although it is thought to arise becauseof impaired antidiuretic hormone secretionaggravated by a nephrogenic component which issecondary to urinary tract dilatation (Cremers et al.,1977). The results in this case fit with this explanation,although whilst the nephrogenic component of thediabetes insipidus was proven, the neurogenic com-ponent was not.

There is no evidence that the urinary tract dilatationin the DIDMOAD syndrome is due to organicobstruction (Page et al., 1976). However there isevidence of functional obstruction as intervention toimprove drainage by self catheterization (Aragona etal., 1983), bladder neck resection (Cremers et al., 1977)or formation of an ideal conduit (Moore, 1971) leadsto an improvement in hydronephrosis. In this caseimproved drainage by bladder neck resection and thenby an ileal conduit led to a fall in blood urea andcreatinine and a reduction in urine volume consistentwith reduced outflow pressure and improved renaltubular function. Page et al. (1976) have suggested that

Protected by copyright.

on Novem

ber 29, 2020 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.62.731.859 on 1 Septem

ber 1986. Dow

nloaded from

862 CLINICAL REPORTS

the high urine flow rate caused by diabetes insipidusleads to progressive passive dilatation of the urinarytract and that this together with inattention to periodicbladder emptying impairs detrusor action producing afunctional obstruction. This explanation is consistentwith the observation that megaureter and megacystisdo occur in both hereditary nephrogenic diabetesinsipidus (Carter & Goodman, 1963; ten Bensel &Peters, 1970) and hereditary anti-diuretic hormonesensitive diabetes insipidus (Pender & Fraser, 1953;Wheeler & Adelson, 1964; Boyd et al., 1980). Urinarytract dilatation does not develop in adult onsetdiabetes insipidus (Fink, 1928; Page et al., 1976) butthis might be because the high flow rate operates over ashorter period or because the childhood tract is moresusceptible to dilatation.An alternative explanation for urinary tract dilata-

tion is that there is a selective neuropathy affecting thebladder and ureters. This could be either a primarydegenerative condition or secondary to diabetesmellitus. The latter is somewhat unlikely as in this caseand in many (Page et al., 1976) but not all (Cremers etal., 1977; Verri et al., 1982) previous cases there was noevidence of diabetic autonomic neuropathy or peri-pheral neuropathy. Immunohistological studies ofneuropathic bladders (Gu et al., 1983, 1984) haverevealed a characteristic picture of proliferating S- 100

staining Schwann cells which was not seen in this case.The Schwann cell proliferation is thought to occurwhen nerve fibre degeneration and regeneration occurconcomitantly. However, a purely degenerativeneuropathy could, in theory, lead to a loss of nervefibres without Schwann cell hyperplasia. In fact focalprogressive neuropathy is in many ways the hallmarkof the DIDMOAD syndrome leading to progressiveoptic atrophy, progressive high tone deafness andimpaired anti-diuretic hormone secretion from thehypothalamus. The marked diminution in nerve fibrestaining observed in the bladder and ureter in this casesupports this concept although the possibility that thedecreased density of nerve fibres is secondary tomuscular hypertrophy cannot be excluded with con-fidence. If there is a primary degenerative neuropathyit is clear that it is focal as immunohistological stainingrevealed a normal density of nerve fibres in theappendix and small intestine.

Further immunohistological studies of the urinarytract in the DIDMOAD syndrome, using a wide rangeof antisera against neurone-specific antigens are re-quired to see if the changes that we have noted are aconstant finding and to determine whether they are thecause of the urinary tract dilatation or a consequenceof it.

References

ARAGONA, F., GARAT, J.M. & MARTINEZ, E. (1983).Urological aspects of Wolfram's syndrome. EuropeanUrology, 9, 75.

BOYD, S.D., RAZ, S. & EHRLICH, R.M. (1980). Diabetesinsipidus and nonobstructive dilation of urinary tract.Urology, 16, 266.

BRETZ, G.W., BAGHDASSARIAN, A., GRABER, J.D., ZACHE-RLE, B.J., NORUM, R.A. & BLIZZARD, R.M. (1970).Coexistence of diabetes mellitus and insipidus and opticatrophy in two male siblings. American Journal ofMedicine, 48, 398.

CARTER, R.D. & GOODMAN, A.D. (1963). Nephrogenicdiabetes insipidus accompanied by massive dilatation ofthe kidneys, ureters and bladder. Journal of Urology, 89,366.

CREMERS, C.W.R.J., WIJDEVELD, P.G.A.B. & PINCKERS,A.J.L.G. (1977). Juvenile diabetes mellitus, optic atrophy,hearing loss, diabetes insipidus, atonia of the urinary tractand bladder, and other abnormalities (Wolfram Syn-drome). Acta Paediatrica Scandinavica, 264, 3.

FINK, E.B. (1928). Diabetes insipidus. Archives ofPathology,6, 102.

GU, J., ISLAM, K.N., HEHIR, M. & POLAK, J.M. (1983). Theincrease of S100 in the neuropathic bladder. Journal ofPathology, 139, 502.

GU, J., POLAK, J.M., DEANE, A., COCCHIA, D. & MICHETrI,F. (1984). Increase of S-100 immunoreactivity in theurinary bladder from patients with multiple sclerosis, anindication ofperipheral neuronal lesion. American Journal

of Clinical Pathology, 82, 649.GU, J., HUANG, W.M. & POLAK, J.M. (1985). Stability ofimmunocytochemical reactivity of neuronal substancesfollowing delayed fixation. Journal ofNeurosciences Meth-ods, 12, 297.

MARQUARDT, J.L. & LORIAUX, D.L. (1974). Diabetesmellitus and optic atrophy. Archives ofInternal Medicine,134, 32.

MOORE, J.R. (1971). Juvenile diabetes mellitus, diabetesinsipidus and neurological abnormalities. Proceedings ofthe Royal Society of Medicine, 64, 730.

PAGE, M. Mc B., ASMAL, A.C. & EDWARDS, C.R.W. (1976).Recessive inheritance ofdiabetes: the syndrome ofdiabetesinsipidus, diabetes mellitus, optic atrophy and deafness.Quarterly Journal of Medicine, 179, 505.

PENDER, C.B., & FRASER, F.C. (1953). Dominant inheritanceof diabetes mellitus. Pediatrics, 11, 246.

RAITI, S., PLOTKIN, S. & NEWNS, G.H. (1963). Diabetesmellitus and insipidus in two sisters. British MedicalJournal, 2, 1625.

ROSE, R.C., FRASER, G.R., FRIEDMAN, A.I. & KOHNER,E.M. (1966). The association of juvenile diabetes mellitusand optic atrophy; clinical and genetical aspects. QuarterlyJournal of Medicine, 139, 385.

STERNBERGER, L.A. (1979). The unlabelled antibody perox-ide anti-peroxidase (PAP) method. In Immunocytochemis-try, Sternberger, L.A. (ed). p. 104-169. John Wiley: NewYork.

TEN BENSEL, R.W. & PETERS, E.R. (1970). Progressive

Protected by copyright.

on Novem

ber 29, 2020 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.62.731.859 on 1 Septem

ber 1986. Dow

nloaded from

CLINICAL REPORTS 863

hydronephrosis, hydroureter and dilatation of the bladderin siblings with congenital nephrogenic diabetes insipidus.Journal of Pediatrics, 77, 439.

VERRI, A., BORUTITI, G., SANDRINI, G., POLONI, M. &VAILATI, A. (1982). A case of Wolfram syndrome:neurological features. Italian Journal of NeurologicalSciences, 4, 351.

WHEELER, J.S. & ADELSON, W.J. (1964). Pituitary diabetesinsipidus associated with progressive urinary tract dilata-tion. Journal of Urology, 92, 64.

WOLFRAM, D.J. (1938). Diabetes mellitus and simple opticatrophy among siblings: Report of four cases. Proceedingsof the Staff Meetings of the Mayo Clinic, 13, 715.

Protected by copyright.

on Novem

ber 29, 2020 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.62.731.859 on 1 Septem

ber 1986. Dow

nloaded from