DIDMOAD (WOLFRAM) SYNDROME

1075

healthy infants who come from populations with an unusually early peak incidence of meningitis,ls,l6 combined passive and active immunisation could provide uninterrupted protection while nasopharyngeal colonisation proceeds and local or systemic immunity develops. Availability of purified hyperimmune globulin may also lead to reappraisal of serotherapy for severe Hib infections. 18 Whilst the polysaccharide vaccine is available in the USA 19 in other

and has been recommended for use in children over 2 years old,2° the benefits of vaccination must be carefully weighed in each country before widespread immunisation campaigns are adopted. An ideal Hib vaccine would have the potential for worldwide eradication of the disease. Meanwhile, it is important to gain a better understanding of the epidemiology and pathogenesis of Hib infections.

DIDMOAD (WOLFRAM) SYNDROME THE DIDMOAD syndrome in its original form, as reported by Wolfram,’ described the association of diabetes mellitus (DM) and optic atrophy (OA), but lacked the diabetes insipidus (DI) and deafness (D) components. It is now recognised that sensorineural deafness or abnormal audiometry occurs in at least 39% of cases, central DI in 32%, and dilatation or atony of the lower urinary tract in 15%,2 with many other abnormalities described in small numbers of patients. Family studies often indicate an autosomal recessive mode of inheritance. With the exception of one report in which members of successive generations of a family were affected,3 multiple cases in any one family are found only in siblings, consanguinity in marriage has been recorded in at least 23% of studies, 2,4 sex incidence is equal, and the ratio of affected to unaffected siblings approximates 1 to 3. Insulin-dependent and ketosis-prone DM typically develops at an early age, but the onset is not abrupt5 and two subjects have not required insulin.6,7, Islet-cell autoantibodies8,9 have not been detected. C-peptide concentrations are low and unresponsive to stimulation,5,s,1O and there are no histopathological descriptions of the pancreatic islets.’ 1,12 Whilst features characteristic of long-standing DM (retinopathy, neuropathy) are rare,13-15 it is unclear whether this merely reflects the rather short duration of DM at the 18 Alexander HE. Treatment of H influenzae infections and of meningococcic and pneumococcic meningitis. Am J Dis Child 1943; 66: 172-87. 19. Pharmaceutical Supplies Bulletin 1985. vol 8, no 5. 20. FDA soon to license H influenzae vaccine. JAMA 1985, 253: 1232-33. 1. Wolfram DJ. Diabetes mellitus and simple optic atrophy among siblings: Report of four cases Proc Mayo Clin 1938; 13: 715-18. 2. Cremers CWRJ, Wijdeveld PGAB, Pinckers AJLG. Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder, and other abnormalities (Wolfram syndrome). Acta Paed Scand 1977; suppl 264: 3-16. 3. Shaw DA, Duncan LJP. Optic atrophy and nerve deafness in diabetes mellitus. J. Neurol Neurosurg Psychiatr 1958; 21: 47-49 4 Page MM, Asmal AC, Edwards CRW. Recessive inheritance of diabetes: The syndrome of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Quart J Med 1976; 45: 505-20. 5. Peden NR, Gay JDL, Jung RT, Kuwayti K. Wolfram (DIDMOAD) syndrome: A complex long-term problem in management. Quart J Med 1986; 58: 167-80. 6. Gunn T, Bortolussi R, Little JM, Andermann F, Fraser FC, Belmonte MM. Juvenile diabetes mellitus, optic atrophy, sensory nerve deafness, and diabetes insipidus— Pediatr 1976; 89: 565-70. a syndrome. J 7 Richardson JE, Hamilton W. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness: 3 cases of "DIDMOAD" syndrome. Arch Dis Child 1977; 52: 796-98. 8 Wilson JD, Simpson RW, Wahlqvist ML, Favilla I, Tait BD Familial optic atrophy with diabetes mellitus. Aust NZ J Med 1982; 12: 48-51. 9 Monson JP, Boucher BJ HLA type and islet cell antibody status in family with (diabetes insipidus and mellitus, optic atrophy and deafness) DIDMOAD syndrome. Lancet 1983; i: 1286-87. 10. Lessell S, Rosman NP. Juvenile diabetes mellitus and optic atrophy. Arch Neurol 1977; 34: 759-65. 11. Carson MJ, Slager UT, Steinberg RM. Simultaneous occurrence of diabetes mellitus, diabetes insipidus and optic atrophy in a brother and sister. Am J Dis Child 1977; 131: 1382-85. 12 Karp M, Laron Z, Sandbank U. Wolfram syndrome. Am J Dis Child 1978; 132: 818-19.

time of examination, or whether the patients are protected from chronic diabetic complications. HLA haplotypes associated with typical insulin-dependent DM (B8, B15, DR3, DR4) are absent, and reports of an association with DR2s,9,16 have not been confirmed by all investigators.15 Of more importance to the patients than the small risk of diabetic retinopathy, is the virtually inevitable development of one of the cardinal features of the syndrome, optic atrophy, with attendant loss of vision. The optic atrophy is usually associated with defective colour vision and progressive, concentric limitation of peripheral visual fields,2,lo,14,17,18

central

scotomas are found normal intraocular pressure, the optic nerve head is commonly excavated.1O Granular retinal pigmentation, which may precede visual loss by several years, has also been described.6,13-15 In the few cases with postmortem reports, pronounced atrophy of the entire optic system20 and of the pons have been noted, 11,12 associated with severe axonal degeneration and demyelination without gliosis. In a 16-year-old patient with clinical optic atrophy2 in whom visual acuity was 3110, the optic system showed slight gliosis and loss of myelin structure without signs of active demyelination. Failure to demonstrate gliosis in these atrophic optic systems is consistent with primary optic atrophy. Whether degeneration of the ganglion cell layer and optic nerve fibre layer occurs in conjunction with or as a result of optic atrophy I7 remains to be established. Demyelination and axonal degeneration of the pons and its connections have been regarded as typical of the changes seen in olivopontocerebellar degeneration," with the suggestion that the ataxia which characterises clinical onset of that condition (mean age 38 years) might have become manifest had the DIDMOAD patients survived. Although the rate of progression to near or total blindness varies, the median age of onset of visual impairment (11 years2), together with development of deafness in a smaller proportion of patients, inevitably restricts educational and career prospects. In contrast to the devastating visual deterioration, deafness is not universal, and may be detected only as a high frequency (>4000 Hz) bilateral sensorineural hearing loss which, if progressive, extends to affect the lower frequencies.2,5,15 This may be due to a degeneration of the stria vascularis, but with sparing of the retrocochlear portion of the auditory system. 15s The frequency of DI (32%), the final cardinal feature of this syndrome, may be a considerable underestimate, since the polyuria may have been erroneously attributed to poorly controlled DM. Median age of onset of DI is 12 years, similar

although

or

paracentral

occasionally.2,15,19 Despite

FC, Fraser GR, Friedmann AI, Kohner EM The association of juvenile diabetes mellitus and optic atrophy: Clinical and genetical aspects Quart J Med 1966, 35: 385-405. Rorsman G, Söderström N. Optic atrophy and juvenile diabetes mellitus with familial occurrence. Acta Med Scand 1967; 182: 419-25. Najjar SS, Saikaly MG, Zaytoun GM, Abdelnoor A. Association of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. The Wolfram or DIDMOAD syndrome. Arch Dis Child 1985, 60: 823-28 Deschamps I, Lestradet H, Schmid M, Hors J. HLA-DR2 and DIDMOAD syndrome. Lancet 1983; ii: 109. Niemeyer G, Marquardt JL. Retinal function in an unique syndrome of optic atrophy, juvenile diabetes mellitus, diabetes insipidus, neurosensory hearing loss, autonomic dysfunction and hyperalanineuria. Invest Ophthalmol 1972; 11: 617-24. Ikkos DG, Fraser GR, Matsouki-Gavra E, Petrochilos M. Association of juvenile diabetes mellitus, primary optic atrophy and perceptive hearing loss in three sibs, with additional idiopathic diabetes mellitus insipidus in one case. Acta Endocrinol (Copenh) 1970; 65: 95-102. Marquardt JL, Loriaux DL. Diabetes mellitus and optic atrophy with associated findings of diabetes insipidus and neurosensory hearing loss in two siblings. Arch Intern Med 1974; 134: 32-37. Khardori R, Stephens JW, Page OC, Dow RS Diabetes mellitus and optic atrophy in two siblings: A report on a new association and a review of the literature. Diabetes Care 1983; 6: 67-70.

13. Rose

14. 15.

16. 17

18.

19.

20.

1076 to

DM and visual loss.

obtained; in

some

Responses to vasopressin have been patients, in whom residual endogenous

vasopressin secretion may have been present, antidiuretic (but not hypoglycaemic) responses to chlorpropamide have also been found.4 As might be expected, postmortem examination of the hypothalamus showed neuronal loss in the paraventricular and supraoptic nucleill,12 and an absent or attenuated posterior lobe of the pituitary gland. In patients with hyposmia or anosmia2,1O,19 a similar degeneration of axons and myelin of the olfactory nerve and its connections has probably occurred. A substantial proportion of patients have dilatation of the lower urinary tract-from mild hydroureter or hypertrophic, atonic bladder to severe hydronephrosis.This was initially attributed to myelopathy or bladder outlet obstruction,l3 or to the high urinary output of DI, since dilatation improved with satisfactory control of DI.4 However, since dilatation may occur in the absence ofDI,15 degeneration of the nerve supply to ureters and bladder may be the primary cause.5 In view of the significant morbidity and mortality from renal failure associated with recurrent urinary infections, I 1,20 Peden and his colleagues in Dundee have again drawn attention to this manifestation of the syndrome, which may be amenable

to

active

management.5

The Dundee group

emphasise the defective fertility which may occur in patients of both sexes. Of the female patients for whom information was available in the literature, almost half had abnormalities of menstruation, or of uterine or pubertal development.5 Nevertheless, Peden et al were able to report the first successful pregnancy in a patient with the syndrome. Since the DI is caused by a hypothalamic lesion it might have been expected that infertility would also be central (hypothalamic) in origin. However, at least in male patients who have been investigated appropriately, the reverse appears to be the case-20% of adult males described in the literature were noted to have small testes or to be hypogonadal, and defective spermatogenesis was invariably demonstrated in those in whom biopsies were done. In two pubertal male patients reported by the Dundee workers, levels of luteinising hormone were significantly increased in one and of folliclestimulating hormone in both,5 supporting the diagnosis of primary Leydig cell and seminiferous tubular dysfunction rather than a hypothalamo-pituitary cause of

hypogonadism.2’ The

precise genetic defect in this multi-system degenerative disorder is unknown and it is questionable whether significant progress in defining a marker of the carrier state or of the presumed biochemical defect may be anticipated in the near future. Nevertheless, as patients with this non-lethal disorder survive longer, it is important that the diagnosis should not be missed in cases of atypical DM in children or adolescents. Awareness and anticipation of disease manifestations in other systems, chiefly the urinary tract, may alleviate morbidity considerably. Sadly, it seems unlikely that loss of vision can be prevented, and management must remain supportive.

images of the

cancer

DISQUIET that the many and varied techniques for treating breast carcinoma were not producing a significant reduction in mortality led to emphasis on early diagnosis of the disease and hence to exploration of methods for producing diagnostic 21. Handelsman

DJ, Swerdloff RS Male gonadal dysfunction. Clin Endocrinol Metab 1985, 14: 89-124

Mammography

is

effectively the gold

by mammographic screening can reduce the mortality

of the disease. Other techniques for producing breast include thermography,

of the transillumination or diaphanography, magnetic resonance imaging, and sonar scanning or sonomammography. The latest method, as yet incompletely assessed, is microwave thermography. Of these various techniques, only sonomammography has been shown capable of a diagnostic accuracy comparable with that of mammography. Should it be adopted more widely? Smallwood and his colleagues from Southampton show that the enthusiastic and meticulous application of sonomammography can produce very accurate diagnostic information6-and this despite the fact that ultrasound cannot resolve microcalcifications and that its capacity for resolving small carcinomas is limited. The Southampton series, however, does include lesions which are significantly less than 5 mm in diameter. It is worth remembering that mammography can only achieve the highest sensitivities quoted in the literature when obsessive attention is paid to all stages of production and reading of the mammograms. The same is certainly true with the use of sonar scanning, and there is perhaps some slight suspicion that the Southampton workers’ enthusiasm for ultrasonography is not quite matched by their enthusiasm for mammography. Certainly one lesson to be learned from many of the publications on diagnostic techniques in breast disease is that the very highest standards must be set initially in the production of the diagnostic image, and that rigorous quality control must be applied thereafter to maintain that high quality. However, such standards represent a significant drawback in the implementation of widespread screening for breast cancer. A truly satisfactory screening modality has yet to be found-such a technique must be easy to apply, easy to interpret, and have wide latitude in the standard of performance of the test without significant degradation of the results obtained. These criteria do not apply to sonomammography as we know it today. As Smallwood et al note, it is difficult to define the role to be played by a new diagnostic technique; certainly with the equipment presently available, the conclusion that the major role for sonomammography is in the investigation of abnormalities detected either clinically or by mammography is

diagnostic images

undoubtedly correct.

BB, Kirkpatrick AE, Roberts MM, Duffy SJ. Single oblique mammography; Adequacy for screening. Radiology 1984; 151: 39-41 2 Tabar L, Fagerberg CJG, Gad A, et al. Reduction in mortality from breast cancer after mass screening with mammography. Lancet 1985, i 829-32. 3. Shapiro S, Venet W, Strax P, Venet L, Roelser R Ten-to-fourteen year effect of screening on breast cancer mortality. JNCI 1982; 69: 349-55. 4. Verbeek ALM, Hendriks JHCL, Holland R, et al Reduction of breast cancer mortality through mass screening with modern mammography Lancet 1984; n: 122-24 5. Collette HJA, Day NE, Rombach JJ, de Waard F Evaluation of screening for breast cancer in a non-randomised study (the DOM project) by means of a case-control study. Lancet 1984; ii 1224-26. 6. Smallwood JA, Guyer P, Dewbury K, et al The accuracy of ultrasound in the diagnosis of breast disease. Ann R Coll Surg Engl 1986; 68: 19-23. 1 Muir

SONOMAMMOGRAPHY

breast.

standard in this field. Studies both in the UK’ and in continental Europe, particularly Sweden,2 have shown that in screening a population of well women, especially those above the age of fifty, mammography has a sensitivity of between 91% and 95% for detection of breast cancer. Studies carried out in New York,3 Sweden,2 and Holland’have all provided evidence indicating that early detection of breast