MR Findings in Oculocerebrorenal Syndrome

William J. Carroll,1 William W. Woodruff,1 and Thomas E . Cadman2

Summary: Oculocerebrorenal syndrome is an X-linked recessive OCRS was made at age 6 months. Development in all disorder characterized by congenital ocular abnormalities, men­ mental spheres was slow. There was no history of regres­ tal retardation, renal disease, and metabolic bone disease. We sion. The child sat at 3 years and began walking at 5 years. report a case of oculocerebrorenal syndrome and, using Tl-, Pa st medical history included bilateral cataract surgery and proton density-, and T2-weighted imaging sequences, are able glaucoma. to characterize two distinct white matter abnormalities: one Physical examination revealed a small, thin boy whose lesion is punctate and has signal characteristics that parallel height (96 em) and weight (15.4 kg) were below the 3rd that of cerebrospinal fluid; a second lesion, found in association percentile. The child exhibited self-stimulatory activity and with the first, consists of patchy white matter abnormalities was noted to operate in the profoundly retarded range. that are hypointense on Tl-weighted images but hyperintense There was evidence of bilateral eye surgery. Vision was on proton density- and T2-weighted images. markedly impaired. There was no evidence of glaucoma. Deep tendon reflexes were hypoactive. There was hypo­ Index terms: Familial conditions; White matter, abnormalities; tonia of all extremities with bilateral proximal leg weakness. Pediatric neuroradiology; Degenerative brain disease The patient's blood urea nitrogen, creatinine, and electro­ lytes were normal. Creatinine phosphokinase was elevated Oculocerebrorenal syndrome (OCRS), as first (762 lU/ L; normal = 24-1 95). An electroencephalogram described by Lowe et al (1), is an X-linked reces­ was grossly abnormal with slowing of the background sive disorder whose etiology has yet to be deter­ activity. Multifocal spike and polyspike activity in addition mined. Recent gene mapping, however, suggests to generalized spike wave paroxysms were noted. the probable gene site at Xq24-26 (2, 3). The Tl-weighted MR images showed supratentorial white primary clinical manifestations of OCRS include matter abnormalities consisting of multiple, bilateral, well­ congenital ocular abnormalities, mental retarda­ defined foci isointense to cerebrospinal fluid (Fig. 1A). tion, renal tubular dysfunction (Fanconi syn­ Subtle regions of decreased signal intensity surrounded drome), and metabolic bone disease (1, 4-6). many of the lesions (Fig. 1 B). Proton density- and T2- weighted images (Figs. 1C-1 F) show more extensive con­ Therapy is supportive and is aimed both at treat­ fluent foci of increased signal present throughout the white ment of ophthalmologic sequelae and at nutri­ matter extending from the subcortical region to the ven­ tional replacement of renal losses. Although the tricular surface. clinical and laboratory findings of OCRS are well documented, there are only a few imaging inves­ tigations that have used magnetic resonance (MR) Discussion to evaluate these patients (7-9). We present a The cranial MR findings in our patient consist case of OCRS and describe the cranial MR find­ of diffuse supratentorial white matter abnormali­ ings. ties. Tl-, proton density-, and T2-weighted im­ ages confirm the presence of two distinct lesions. Case Report The first of these is characterized by multiple small spherical foci in deep and subcortical white 1 A 7 /2 -year-old white boy was referred for evaluation matter. The signal characteristics of these foci and treatment of seizures. Seizure activity was first noted approximately 6 months prior to presentation and con­ parallel that of cerebrospinal fluid on all three sisted of unresponsiveness and clonic movements of the spin-echo sequences. These discrete abnormali­ upper extremities followed by generalized hypotonia. The ties were found in association with the second child was born at full term weighing 2.8 kg. A diagnosis of type of lesion that was characterized by confluent

Received January 27 , 1992; revision requested February 20; revision received May 21 and accepted June 26. 1 Department of Radiology, The Geisinger Medical Center, 100 North Academ y A ve. , Danville, PA 17822. Address reprint requests to W. W. Woodruff. 2 Department of Pediatric Neurology, The Geisinger Medical Center, 100 North Academy A ve., Danville, PA 17822.

AJNR 14:449-451 , Mar/ Apr 1993 0195-6108/ 93/ 1402-0449 © Ameri can Society of Neuroradiology 449 450 CARROLL AJNR: 14, March/April 1993

Fig. 1 . A and B, Parasagittal and axial Tl-weighted images (350/15) (TR/TE) demonstrate multiple, well-defined foci isointense to cerebrospinal fluid (arrows) surrounded by regions of decreased sig­ nal intensity (open arrows). Cand D, Axial proton density- (2500/ 30) and T2-weighted (2500/90). The punctate lesions (arrows) identified on the T ]-weighted sequence remain isoin­ tense to cerebrospinal fluid. Confluent high signal (open arrows) surrounded the punctate lesions sparing the subcortical U-fibers. E and F, Coronal proton density­ (2500/30) and T2-weighted (2500/90). The punctate high intensity foci (arrows) are surrounded by confluent high signal (open arrows).

A B

c D

E F AJNR: 14, March/ April 1993 MR OF OCULOCEREBRORENAL SYNDROME 451 areas of abnormal signal intensity. These con­ the leukodystrophies including Alexander dis­ fluent regions show diffuse involvement of the ease, Canavan disease, Krabbe disease, Pelizaeus­ white matter with extension to the subcortical Merzbacher disease, and metachromatic and ad­ surface and are slightly hypointense on T1- renoleukodystrophy can produce diffuse white weighted images and hyperintense on both pro­ matter abnormalities. Similarly, multiple scle­ ton density- and T2-weighted images. Neither rosis, the mucopolysaccharidoses, and the met­ lesion was associated with mass effects. abolic amino-acidurias (OCRS is a variant of renal Several recent case reports (7 -9) have de­ Fanconi syndrome) produce deep and cortical scribed similar diffuse confluent white matter white matter abnormalities. Finally, infectious, hyperintensities OCRS patients. Our manuscript hypoxic, and traumatic etiologies can produce describes both T1- and T2-weighted abnormali­ extensive white matter changes. Although the ties and characterizes two distinct lesions based cranial MR findings reported here are not specific on their signal characteristics. for OCRS, the constellation of clinical, laboratory, Although the focal white matter abnormalities and imaging finds are. Our patient exhibited described above point to the presence of two many of the typical clinical features of a child lesions, without histologic confirmation one can with OCRS including the characteristic ocular only speculate on their morphologic correlates. findings, mental retardation, profound develop­ We believe that both lesions represent chronic mental delay, seizures, myopathy, and growth processes and that the smaller punctate lesions retardation. represent focal areas of encephalomalacia per­ haps arising secondary to remote insult. The confluent lesions, however, do not exhibit the References signal characteristics of fluid. These white matter hyperintensities probably represent focal areas of 1. Lowe CU, Terrey M, Macl achlan EA. Organ ic-aciduri a, dec reased gliosis or demyelination. Unfortunately, the neu­ renal ammonia production, hydrophthalmos, and mental reta rdation: a clinica l entity. Am J Dis Child 1952;83: 164- 184 ropathologic data are derived from a limited num­ 2. Wa ldelius C, Fagerholm P, Pe ttersson U, Anneren G. Lowe oculocer­ ber of gross and histologic autopsy specimens. ebrorenal sy ndrome: DNA-based linkage of the gene to Zq 24- q26, These data ( 10-13) are extremely variable and using tightly linked fl an king markers as the correlation to lens were obtained prior to the advent of MR. examination in ca rrier diagnosis. Am J Hum Genet 1989;44:24 1-247 Habib et al ( 10) have described a primary 3. Sil ver ON, Lewis RA, Nussbaum RL. Mapping the Lowe oculocere­ demyelinating process involving both the cere­ brorenal syndrome to Xq24-q26 by the use of restri ction fragment length polym orphism s. J Clin In vest 1987;79:282-285 brum and cerebellum that they attribute to a 4. Charnas LR , Bernad ini I, Rader D, Hoeg JM, Ga hl WA. Clin ica l and toxic metabolic effect. Matin and Schlote ( 11) in laboratory findin gs in the oculocerebrorenal syndrome of Lowe with a review of histologic slides from three patients special reference to growth and renal function. N Eng/ J Med (including a histologic specimen obtained from a 1991;324: 1318- 1325 child previously reported by Habib and cowork­ 5. Abbassi V, Lowe CU. Oculo-cerebro-renal syndrome. Am J Dis Child ers) with OCRS also reported abnormalities that 1968;1 15: 145- 168 6. Loughead HL, Mimouni F, Schill ing S, Feingold M. Picture of the primarily involved white matter. However, they month. Am J Dis Child 1991 ;145:1 13-1 14 noted that the white matter pallor was largely a 7. O 'Tauma DA, Lasker OW. Oculocerebrorenal sy ndrome: case report result of reactive gliosis. Except for several tiny with CT and MR correlates . AJNR 1987;8:555-557 foci in the case reported by Habib et al ( 10), no 8. Charnas L, Bernar J , Pezeshkpour GH, Dalaka s M , Harper GS, Ga hl active demyelination was noted. Thus, they con­ WA. MRI findings and periphera l neuropathy in Lowe's sy nd rom e. clude that, at least in older children, the myelin Neuropediatrics 1988; 19:7- 9 9. Ga brielli 0 , Salvolini U, Coppa GV, et al. Magnetic resonance imaging pallor corresponded to gliosis. Matin and Sylves­ in the malformative syndromes with mental retardation. Pediatr Radio/ ter (12) found decreased myelin content in white 1990;2 1: 16-19 matter tracts of the cerebellum and brain stem 10. Ha bib R, Bargetyon E, Bri ssa ud HE, Ra ynaud J , de Ball JC. Consta­ and did not comment on any specific abnormal­ tations anatomiques chez un enfa nt atteint d'un syndrome de Lowe. ities involving the white matter of the cerebrum. Arch F Pediatr 1962; 19:945- 960 Conversely, Richards et al (13) noted that the 11. Malin JJ, Schlote W. Central nervous system lesions in disorders of most striking abnormalities involved the cortical amino acid metabolism . J Neural Sci 1972; 15:26-29 12. Matin MA, Sylvester PE. Clinicopathologica l studies of oculocerebro­ gray matter, although they too noted gliosis in­ renal sy ndrome of Lowe, Terry, and Macl achl an. J Ment Defic Res volving the white matter of the cerebrum. 1980;24: 1- 16 The white matter hyperintensities reported 13. Ri chards W, Donnell GN, Wilson WA, Stowens D, Perry T. The oculo­ here represent a nonspecific finding. Several of cerebro-rena l sy ndrome of Lowe. Am J Dis Child 1965; I 09: 185-200