Journal of Neuro-Ophthalmology, December 1982, Volume 2, Issue 4

Progressive visual loss, diabetes mellitus, and associated abnormalities (DIDMOAD syndrome).

A syndrome including juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and high-frequency sensorineural hearing loss, expressed completely or partially, is being identified with greater frequency. Visual loss may be progressive and accompanied by primary optic atrophy. Concurrent diabetic retinopathy has only rarely been reported. Visual acuity may deteriorate to less than 20/400. The etiology is unknown. However, histopathologic studies indicate that the diabetes insipidus, optic atrophy, and neurosensory hearing loss represent progressive degenerative conditions. Inheritance appears to be autosomal recessive with incomplete penetrance. The syndrome is rare; therefore, a complete neuroophthalmologic and neuroradiologic evaluation is imperative to rule out a mass lesion. This syndrome should be considered in young people with visual loss and optic atrophy of unknown etiology even if they are not known juvenile diabetics.

]. Clin. Neuro-ophth'llmol. 2: 241-244, IQt\2. Progressive Visual Loss, Diabetes Mellitus, and Associated Abnormalities (DIDMOAD Syndrome) GARY A. KOCHER, MD. THOMAS C. SPOOR, MD., M.5. JAMES G. FERGUSON, JR., MD. Abstract A syndrome including juvenile-onset diabetes melli­tus, optic atrophy, diabetes insipidus, and high-fre­quency sensorineural hearing loss, expressed com­pletely or partially, is being identified with greater frequency. Visual loss may be progressive and accom­panied by primary optic atrophy. Concurrent diabetic retinopathy has only rarely been reported. Visual acu­ity may deteriorate to less than 20/400. The etiology is unknown. However, histopathologic studies indicate that the diabetes insipidus, optic atrophy, and neuro­sensory hearing loss represent progressive degenera­tive conditions. Inheritance appears to be autosomal recessive with incomplete penetrance. The syndrome is rare; therefore, a complete neuroophthalmologic and neuroradiologic evaluation is imperative to rule out a mass lesion. This syndrome should be consid­ered in young people with visual loss and optic atro­phy of unknown etiology even if they are not known juvenile diabetics. Introduction An association has been reported between ju­venile- onset diabetes mellitus, optic nerve atrophy, high-frequency sensorineural hearing loss, diabe­tes insipidus and, in some cases, nystagmus, neu­rogenic bladder, hydronephrosis, and hyperalani­nuria. l-I:l This disorder has been designated as Marguardt-Loriaux's syndrome,1t and Wolfram's syndrome, Ie, but the acronym DIDMOAD syn­drome (Diabetes Insipidus, Diabetes Mellitus, Op­tic Atrophy, and Deafness),'; has also been used. Although ocular stigmata-optic atrophy, dyschro­matopsia, visual field abnormalities, abnormal pu­pillary findings, and progressive visual loss-are major components, this syndrome has received From the Division of Ophthdlmology (CAK, TCS, ICF), De­partment of Surgery, Unive"ity of South CJr,,/in,l S"h",,/ "f Medicine. Columbia, South Cdcolind. December 1982 little attention in the recent ophthalmic literature. Consequently, it is rarely included in the differ­ential diagnosis of progressive visual loss in juve­nile diabetics. We describe a patient with DID­MOAD syndrome and review the literature in an attempt to heighten clinical awareness of this syn­drome. Case Report A 16-year-old girl with juvenile-onset diabetes mellitus was referred to the ophthalmology service for evaluation of progressive visual loss. She was the product of a normal pregnancy and delivery. At age 10, she developed insulin dependent dia­betes mellitus. Four years later, visual acuity was documented at 20/70 in both eyes by an optome­trist. The following year, urologic evaluation for recurrent urinary tract infections revealed dupli­cation of the left kidney, The accessory kidney was subsequently removed, Several months later, she developed sufficient bladder dysfunction to re­quire daily catheterization. At age 16, she became pregnant and elected to have an abortion. During this hospitalization she was referred for evaluation of decreased vision. Family history revealed a ma­ternal grandmother with adult-onset diabetes mel­litus. Her only sibling, a 14-year-old brother, has no evident ocular, neurologic, or metabolic disease. General physical examination revealed a well-de­veloped female with normal secondary sexual char­acteristics. She had no external congenital abnor­malities or evidence of endocrine dysfunction. Ophthalmic examin,ltion revealed a visual acuity of 20/200 in both eyes ,md marked dyschromatop­sia. Ocular adnexa and extraocular motility were normal. Both pupils responded sluggishly to light. Ne.u reaction W.1S normal. There was no miosis to 1/8% pilocarpine, Slitiamp examination and intra­ocular pressure were normal. Funduscopy revealed pale, sharply defined optic discs without evidence of pathologic cupping, edema, hemorrhage, or op- 241 tllcili.Hy shunt vessels. There W,lS nll evidence llf di,lbdic rdinllp,lthy ,1Ild ,1 flullreslein ,1Ilgillgr,lm W,lS 11l1rm,11. ViSU,ll fields denlllnstr,lted bilater'll, rel.ltive, lTntr,ll, ,1I1d p,lr,lll'ntr,ll sllltllm,lt,l. ~kull ,--r,IVS, l'L1mputerized tllmllgr,lphy llf br,lin and llrbits, ,1I1d plllytnnlllgr,lIlls llf the l>ptic canals were Illlrm,ll. V[)RL ,1Ild ITA-AH~ ll'.,ts were Ileg,ltive. An 'llIdil1gr,1I11 reve,lled high-frequency sensori­neur, ll IW.Hing IllSS. Neurologic ex,lIllin,ltion was lltherwise norm,ll e'-cept fllr bl,ldder dysfundilln. Discussion Our p,ltient is ,1 juvenile-onset diabetic with llptic ,ltrophy who had suffered a slowly progres­sive visu,llioss over 3 vears without a demllnstrable etil1ll1gy. The concurr~nceof juvenile diabetes mel­litus and optic atrophy is infrequently observed ,1I1d W,lS considered fortuitous. lh More recently, this association has been documented and re­viewed in the neurologic literature, 1 as has its tendency for multisystem involvemenl. 17 A review of the literature revealed over 100 sufficiently doc­umented reports of juvenile-onset diabetes melli­tus associated with optic atrophy and other symp­toms excluding those with syndromes such as Friedrich's ataxia and Refsum's syndrome or mass lesions. All of these patients had juvenile diabetes mellitus which was the initial manifestation in 78%. The associatioll of juvenile diabetes mellitus with this syndrome has been reported in approximately 1 of 150 patients.:! However, Fraser and Cunni" more recently presumed the true frequency to be lower than the frequency reported from diabetic clinics by calculating the frequency of homozy­gotes for this syndrome. Studies have been done to determine whether the juvenile diabetes mellitus in this syndrome is identical to that with the usual presentation. The pancreatic beta cell-secreting response to oral glu­cose, isoproterenol, arginine hydrochloride, and tolbutamide was lacking and thus identical to that found in a control group of patients with cbssic juvenile diabetes mellitus. 1The diabetes associated with this syndrome does differ from classic juve­nile diabetes mellitus in that the in vitro life Sp,lll of cultured skin fibroblasts are the S,lllll' in p,ltients with this syndrome as in nondiabetic controls.:! Fibroblasts cultered from juvenile diabetics usu,lllv show a shortened life sp,ln. . Primary llptic nerve ,ltrophv W,lS present in ,111 patients. Funduscopy reve'lled p,lle, sh.Hplv de­fined optic discs without cupping, hemllrrh,lge, optociliary shunt vessels, or disc edem,l. Extensive neuroradiologic evalu,ltions were uniformlv neg,l­tive." II. I:,. 17 :!II Rdinal functil1n in these ~<ltients was evaluated with psydlOphvsic,ll ,1Ild electro­physillillgic testing, I" reve,lling m.Hkedlv reduced ViSU,ll acuity, cllnstricted visual fields,' dvschro­m, ltllp"i,l, ,1Ild elev,lted rod ,1Ild cone th resholds in dark adaptation. The presence of an almost normal rod electroretinogram and moderately reduced cone electroretinogram suggests a descendmg rather than an ascending disease process. These characteristics would implicate involvement of the ganglion cells, nerve fiber layer, and possibly the inner nuclear layer of the central retina by trans~ synaptic degeneration. Histopathologic studies·l have demonstrated severe axonal degeneration and demyelination of the optic nerve, chiasm, tract, and radiations. No gliosis, inflammatory cells, macro­phages, or abnormal storage material were evi­dence nor are any retinal findings mentioned. Cenerally, visual loss is severe and progressive; visual acuity when first examined being 20/200 or worse bilaterally, subsequently deteriorating to hand motion or light perception. Dyschromatopsia is profound. Severe concentric constriction of the peripheral fields is nearly always present and ce­cocentral scotomas are observed early. Pupillary reactions are sluggish or absent to light with normal near reaction. I Instillation of dilute cholinergic drugs often causes rapid pupillary constriction, indicating a denervation supersensitivity secondary to a defect in the postganglionic parasympathetic neurons. This associatIOn may be fortuitous since this finding has been reported in a significant number of un selected diabetic patients,:!! and was not present in our patient. Ophthalmoscopy and fluorescein angiography have revealed no evidence for diabetic retinopathy except in two cases re­ported by Rorsam and Soderstrom."" By contrast, Frank~:! has demonstrated that the prevalence of diabetic retinopathv increases vvith age and dura­tion of disease in the classic patient with juvenile diabetes mellitus. Early reports documented an incidence of high­frequency, neurosensory hearing loss of 39%. More recently. using audiography, a 70 ""0 incidence has been reported" I', The hearing loss is at a frequency higher than the speech frequency and is not noticed by most patients but easily detected by audiogra­phv DavenportC1 emphasized the need to test ves­tibular functil1fl; since vestibular and cochlear hair cells develop from the ectodermal otocyst and cl1Chle.u ,1Ild vestibular nerves from th~ neural crest derived ,Koustic ganglion. There is no histo­p, lthl)logic confirmation of the location of the le­sion. Some data indicate a retrocochlear lesion with the nlOst likely site being the eighth nerve involving the afferent fibers from the basal coils. 4. 24."" Di,lbetes insipidus occurs with this syndrome ,1Ild is present in 34% of cases I-I:) Results of dehy­dr'ltion testing are compatible with a partial defect of ADH elaboration in some patients. 2 . 17 Most responded to pitressin therapy.lO· 12 Necropsies re­vealed an absent posterior lobe of the pituitary in one patient and a small attenuated posterior lobe in another.:1 Histopathologic studies of these spec­imens showed moderate neuron loss in the su- Journal of Clinical Neuro-ophthalmology TABLE l. Associated Diseases Reported in P.ltients with DlDMOAD Syndrome pr.lOptic nucleus with severe degeneration of the paraventricular nuclei bilaterally. Other possible manifestation of hypothalamic dysfunction such as disordered temperature regulation, vasomotor in­stability, or hypogonadism have been reported. Other symptoms have been described with this syndrome; however, the associations have been infrequent. A list of these symptoms has been previously described l \-, and is summarized in Table l. Inheritance has not been established. The syn­drome appears to be transmitted as an autosomal recessive with variable expressitivity, i.e., the hom­ozygote expresses diabetes and at least one of the other major components of the triad-either optic atrophy, nerve deafness, or diabetes insipidus. The heterozygote possibly expresses diabetes alone. The basic defect resulting from the pleiotropic actions of this postulated homozygous gene is un­known. This trait does occur in siblings and off­springs with consanguinous parents with increased frequency. 17. I". "'; The segregation rate is approxi­mately 28%, assuming single ascertainment, and this rate is reasonably close to the expected 25% with a normal sex ratio. I" The heterozygote has an increased probability of developing juvenile onset diabetes. Therefore, the siblings of a child with this syndrome have a 25% chance of developing the complete syndrome or partial expression of it and one chance in six of developing juvenile diabetes mellitus. Family members of an affected patient should be screened with glucose tolerance tests, audiograms, and ophthalmologic exams to ade­quately detect this syndrome or a partial expression of it. Heightened clinical awareness of this syndrome will increase its recognition and allow further study of its inheritance and pathophysiology. An audiol- Ptosis Nyst,lgmus C.,t,H,ld riglll('nt.ll~' retilll'p.lthv Intis Lllrim.ll hypl..'sc,,:rditJI1 [leue,lSed ll111tllit\' Hel11l'r.lll1pt.l 1VlPt"lwlll Allllllll.llldurl.l C\'l1l'(l)Tll.l~tl.l lll'1.1yS sc,u.l1 lll,ltULltlll l1 Sm"l1 ,("ture AIl1Clh.l rrhc.l Clliter l·cnlr.t1 Nl'rvllllt., ~lV ... tl'1ll /\t,"',1 St.'j/lln'.., t\b'll'rm,d Ill, [<'I\' 10 l·cntr.ll.1tn'phv III br.\lll Cell, III ,plll,,1 tllild [[c\,.ltl'd Pl'lltclll in ... pill.,1 flUid P",\,l'ili.ltnl" .1bl11lrm,1Iitil"'" HVPl''-ollll.l l )tl",r, Sidl'rllb1.htll'- .11ll'1ll1.1 ~ i\' pt.'rkn ... ltlll Hvdl'llurl'tl'r<., Hvdl'lllll'phnl..,i ... Ll1l.ll dil.lt,ltilll1 llf (lliun Atllnil' ncun..1genil" b1.1ddl'f Kocher, Spoor, Ferguson ogy screen m.1Y give positive results and should be l"lH1sidered in .1 patient with juvenile diabetes mel­litus .1I1d progressive visu.11 loss of unknown etiol­ogy. However, this syndrome must also be consid­ered in young people with visual loss and optic ,ltrophy of unknown etiology even if their diabetes mellitus h.1S not yet been recognized. These arc the most difficult cases to diagnose, often presenting .1t .1 later age and under atypical circumstances. The syndrome is rare; therefore, a complete neuro­ophth. 1lmologic .md neuroradiologic evaluation should be done to rule out a mass lesion. References I. Lessell, 5., and Rosman, N.P.: juvenile diabetes mel­litus ,md optic atrophy. Arch. Neurol. 34: 759, 1977. 2. Cunn, T., Bortolussi, R., Little, j.M., Andermann, F, Frdser, F.C., and Belmonte, M.M.: juvenile diabetes mellitus, optic atrophy, sensory nerve deafness and diabetes insipidus-A syndrome. ]. Pediatr. 4: 565, 197b. 3. Carson, M.j., Slager, U.T., and Steinberg, R.M.: Si­multdneous occurrence of diabetes mellitus, diabetes insipidus and optic atrophy in a brother and sister. Am. I Dis. Child 131: 1382, 1977. 4. Goddon, R, Longin, B., Mavelle, MD., Gilly, R., and Francois, R.: Association de diabetic sucre, po­Iyurodipsie et trouble senoriels. Pediatric 28: .Q9, 1973. 5. Solomon, G.E., Dleinman, C.S., and Sqeifach, P.: Diabetes mellitus, primary optic atrophy and sen­sorineural deafness: A rare syndrome. Conn. Med. 11: 703,1978. 6. Richardson, j.E., and Hamilton, W.: Diabetes insip­idus, diabetes mellitus, optic atrophy, and deafness: Three cases of DIDMOAD syndrome. Arch. Dis. Child 52: 7%,1977 7. Wolfram, D.j.: Diabetes mellitus and simple optic atrophy among siblings: Report of four cases Pwe. Mayo Clin. 13: 715, 1938. 8. Walsh, F.B., dnd Hoyt, W.F.: Clinical Neuro-Oph­thalnwlogy, Vol. 1. Williams and Wilkins Co., Bal­timore, 190 9, p. 917. 9. Shaw, D.A., and Duncan, L.j.P.: Optic atrophy ,llld nerve deafness in diabetes mellitus. I NeuroJ. Neu­wsurg. Psychiatry 21: 47-49,1 958. 10. Turnbridge, R.E., dnd Pdley, RG.: Primdrv optic atrophy in diabetes mellitus. Di.lbetes 5: 295-90, 195b. 11. Tyrer, I.: Case of inf.1ntilism with goitre, diabetes mellitus, ment,ll defect ,llld bil,lter,ll prim,lry optic ,ltrnphy. Med. I Aust. 2: 398-401, 1943. 12. Rose, F.C., Fr,lser, C.R., Friedm,1I1, A.I., ,llld Kelhner, [.M.: The ,lssoci,ltion e,f tuveni!e di,lbetes Illellitus ,1I1d optic .ltrnphv: Clinic,ll ,1I1d genctic,ll ,lSpects. (}. I Med. 139: 385, 19c,c,. 13. Brctz, C. W., Bdghd.lss,lri,1I1, A., Grdber, J.0., Zach­erie, B.U., Noru, R.A., .1I1d Blizz.ud, R.M.: Coexist­encc of di.lbctes mellitus ,1I1d insipidus and optic .ltrnphy in the Ill,lle siblings. Am. 1 Med. 48: 398, 1970. 14. CcC'n,lC'ts, W.j.: Ocul.Jr SyndwnJes (3rd ed.).lea and Febiger, I'hil'ldelphid, 197c" p. 285. December 1982 243 ! I,JI Figure .t. (,J I Alltcrll- p\..)~t(,f111r .... Ubtr.ll'tC'd ,lllglt'gr,lI11 (b I LltCLll .... ubtr,lt tl,J ..ln~I\..lgr..lnl .... hll\\ln~ gl,lnt f1 h ht l J rl 1tlJ ,1ftC'ry ,UH'U­r~' ....m pr\..)]tdlllg mtp the .... el1.1 turtlC,l ,lnd <;upr,l~('ILH ([ .... tern 200 :surgery • • --L prolactin ng/ml 150 100 50 30 • _______~!~J~~~_~~_~~~~~! _ • 3 wks. pre-op 2 mos. 4 mos. I i~lIrl' 5. lll'rUIll PIP1.h till 1,,\'(,1 .... prc- ,lull pl' .... h)pCLltl\'ely Pn,I.Ktln fell tl' one-h.llf the preoperative level the day after surgery ,'lid fwld ,."',It!y t\lI III Lt,,\' .... I \VP \\,lTk .....llld 2. llll)nth .... pll.... h'pl'r.ltl\'cly, the 1('\'('\ W,lS normal. There was ..In unexplalned I'k\'.dll'il I 11"'11111 1'1'·,II'IW1.lll\'I'h Journal of Clinical Neuro-ophthalmology