Neuro-radiology
Neuroradiology (1992) 34:11%121
9 Springer-Verlag1992
Cranial CT and MRI in diseases with D N A repair defects Ph. Demaerel, B. E. Kendall, and D. Kingsley D e p a r t m e n t of Neuroradiology, Hospital for Sick Children, London, U K Received: 13 August 1991
Summary. The CT and MRI appearances of 5 patients with Cockayne's syndrome, 5 with ataxia telangiectasia and i with Fanconi's anaemia are reported. These conditions, together with Bloom's syndrome and xeroderma pigmentosum are regarded as disorders of DNA repair. Characteristic CT and MRI features of Cockayne's syndrome include generalised atrophy, calcification in basal ganglia and dentate nuclei and white matter low density. Neuroradiological findings in the other DNA repair disorders are nonspecific. Key words: Cockayne's syndrome - Ataxia telangiectasia -Fanconi's anaemia- Central nervous s y s t e m - M R I - CT
Cockayne's syndrome, ataxia telangiectasia and Fanconi's anaemia are included in a group of rare diseases, transmitted as autosomal recessive traits and associated with cellular defects limiting the ability to correct damage to DNA. The diagnosis can be made by demonstrating hypersensitivity of skin fibroblasts to the lethal effects of 254 nm ultraviolet (UV) light or ionising radiation with subsequent defects in recovery of DNA synthesis.
Results
The CT and MRI findings are summarised in Table 2.
Cockayne's syndrome (CS) CT was undertaken in 5 patients and MRI also in 3. There was cerebral and cerebellar atrophy in 4 patients with brain stem atrophy on MRI in 3. On CT there were definite low density lesions in the white matter of both cerebral hemispheres in 3 patients, confirmed on MRI, and probable lesions in one. MRI showed these lesions to involve the periventricular and subcortical white matter. There was calcification in the lentiform nuclei in all patients and in the dentate nuclei and subcortical white matter in one.
Ataxia telangiectasia (AT) CT was performed in 5 patients, with additional MRI in one. There was cerebellar atrophy in 4 patients, with discrete calcification on CT in the lentiform nuclei, white Table 1. Patients Case Sex/age Diagnosis
Patients and methods
Eleven patients (4 female, 7 male) aged 3-22 years, were examined by computed tomography (CT) - 10 cases- and magnetic resonance imaging (MRI) - 4 cases. The diagnosis was made by a positive fibroblast irradiation test or identification of chromosomal abnormalities in all cases. The clinical findings are summarised in Table 1. A further patient with undiagnosed chromosomal instability was included (case 12). MR imaging parameters consisted of axial T2-weighted (2500/3000/15/90) and sagittal Tl-weighted (600/15) spinecho sequences in all patients with an additional STIR sequence (3000/23, 85,150) and in axial and coronal planes in one patient.
Neurological features
no.
1
F 7
2 3 4 5 6 7
M 11 F 5 M 4 M 17 M 22 F 13
8 9 10 11 12
M 3 F 21 M 22 M 7 F 3
Cockayne's Syndrome Type I
Hypertonia, FTT, DD, AX, typical facies Cockayne's Syndrome Type I DD, FIT, AX Cockayne's Syndrome Type II DD, FIT, typical fades Cockayne's Syndrome Type I AX, typical facies Cockayne's Syndrome Type I DD, AX, typical facies Ataxia telangiectasia AX Ataxia telangiectasia Nystagmus, AX, conjuncfival telangiectasia Ataxia telangiectasia DD, AX Ataxia telangiectasia DD, AX Ataxia telangiectasia AX Fanconi's anaemia Vertigo, headaches Chromosomalinstability DD, hemiplegia
DD, developmental delay; FTT, failure to thrive; AX, ataxia
118 Table 2. CT and MR findings Case no.
Cerebral atrophy
Cerebellar atrophy
Ventricular dilatation
White matter lesions
Calcification
Brain stem atrophy MR
CT
MR
CT
MR
CT
MR
CT
MR
CT
MR
1
+
+
+
+
+
+
+
+
+ LG, LP?
+
+
2
+++
+++
+++
+++
+++
+++
?
+
+ LG, LP
+
+++
3
+
+
+++
+++
+++
+++
+
+
++ LG, SCW
+
+++
4
-
No
-
No
-
No
-
No
LG, LP
No
-
5
+
No
+
No
+
No
+
No
+ LG, D, F
No
-
6
-
No
+
No
-
-
No
-
7 8
-
No
+ -
+ No
. -
+ LG
No
-
9
-
No
+
No
10 11
-
No
+
-
No
-
12
-
No
-
No .
.
No .
No
?
. No
.
.
-
No
-
No
-
No
-
No
-
No
-
No
-
No
-
No
+
No
-
No
-
No
-
No
-
No
-
No
No
-
+ LG, LP, C
- , absent; + / + + / + + +, mild/moderate/severe; No, not obtained; ?, uncertain; LG, globus pallidus; LR putamen; C, caudate nucleus; F, falx cerebri; D, dentate nuclei; SCW, subcortical white matter
m a t t e r low density and cortical thickening consistent with p a c h y g y r i a and typical of a n e u r o n a l migration defect in one, in w h o m M R I was not p e r f o r m e d .
Fanconi's anaemia (FA) C T was normal.
Discussion
C o c k a y n e ' s s y n d r o m e , first described in 1936, is characterised by g r o w t h disturbances, microcephaly, m e n t a l retardation and a typical facies [1]. T h e p a t h o p h y s i o l o g y and underlying biochemical abnormality r e m a i n o b s c u r e but the genetic defect is associated with an inhibition of D N A synthesis following U V irradiation in fibroblasts cultured f r o m patients. This t e c h n i q u e confirms the diagnosis [2, 3]. Two types of CS are currently distinguished: the classic or acquired type I and the congenital type II, which has an onset in early infancy. T h e r e is overlap b e t w e e n the two types and c o n t r o v e r s y a b o u t their relationship to the cerebrooculofacial skeletal ( C O F S ) s y n d r o m e and the C A M F A K s y n d r o m e [4, 5]. B e c a u s e of their p h e n o t y p i c resemblance, b o t h CS type II and C O F S s y n d r o m e are considered to be part of the same g r o u p of conditions [4]. T h e C A M F A K syndrome, characterized by failure to thrive, cataract, m i c r o c e p h a l y and kyphoscoliosis, is considered to be CS t y p e II with very early onset and m o r e severe clinical manifestations associated with progressive scoliosis [5].
C T findings in CS have b e e n r e p o r t e d in few cases and consist of cortical and cerebellar atrophy, ventricular dilatation, diffuse white m a t t e r changes and calcification of the basal ganglia, dentate nuclei and subcortical white m a t t e r [6]. Calcification of the lentiform nuclei was present in all o u r patients, but i n v o l v e m e n t of the dentate nuclei and white m a t t e r was n o t e d in only one. O n e patient had 3 C T studies which d e m o n s t r a t e d progressive a t r o p h y and calcification of the basal ganglia by the age of 6. T h e y o u n g e s t patient (aged 4) h a d no evidence of atrophy. M R findings have b e e n r e p o r t e d in 8 patients with CS [%12], 3 each of type I and II with two unspecified. A t r o p h i c changes were best appreciated on the sagittal T l - w e i g h t e d images (Fig. 1). Calcification was less easily recognised on M R than on C T but could be appreciated as low signal intensity on T2-weighted images in an area of high intensity on Tl-weighted images (Fig. 2) involving the globus pallidus and p u t a m e n . M R I s h o w e d clearly the distribution of the lesions in the periventricular and subcortical white m a t t e r extending to the arcuate fibers (Fig. 3). A l t h o u g h the posterior parts of the optic radiations m a y be relatively spared [9], this was not evident in our cases. Differentiation b e t w e e n h y p o m y e l i n a t i o n and dysmyelination or d e m y e l i n a t i o n m a y be resolved by serial M R I scans [8, 9]. A t a x i a telangiectasia (AT) or the L o u i s - B a r s y n d r o m e is a multisystem disorder in which telangiectasia, particularly in the conjunctiva, is associated with cerebellar degeneration. T h e r e is a high risk of malignancy, particular of the lymphoreticular system, and of immunodeficiency, rendering these patients m o r e susceptible to bacterial in-
119
Fig.1. Sagittal Tl-weighted MRI (TR/TE = 600/15) in Cockayne's syndrome (a,b). Severe brain stem and cerebellar atrophy Fig.2. Axial CT (a), axial T2-weighted (TR/TE = 2500/90) (b,e) and sagittal Tl-weighted MRI (TR/TE = 600/15) (d) in Cockayne's syn-
drome. Hyperdense calcificationin the basal ganglia on CT appears as low intensity on T2-weighted images (arrow) and a moderately high intensity on the Tl-weighted image (arrow). Note low intensity (arrow) in the subcortical white matter in e representing calcification
fections. Chromosomal aberrations, observed in one of our cases, are inversion of chromosome 7 and abnormalities on chromosome 14 [3]. Serum alpha-faetoprotein is markedly elevated. The typical feature of cerebellar atrophy was present in four of our cases, but calcification of the lentiform nuclei, white matter changes and pachygyric changes, indicating a migration abnormality, noted in our fifth case, have not previously been described (Fig. 4). MRI findings in this condition have not been described; in our patient only cerebeUar atrophy was observed (Fig. 5). Patients with xeroderma pigmentosum (XP) have microcephaly and are mentally retarded. Ataxia, choreoathetosis and spasticity may occur. CT findings include cerebral and cerebellar atrophy with thickening of the calvarium [13, 14]. Lesions of white matter and calcification have not been described.
Fanconi's anaemia (FA) is a progressive pancytopenia with various congenital abnormalities and a predisposition to malignancy. Treatment by bone marrow transplantation from HLA-identical siblings is curative. In our patient with FA no abnormality was demonstrated on CT. Bloom's syndrome (BS) is characterised by growth deficiency, an unusual facies, sun-sensitive facial telangiectasia, an immunological defect and a predisposition to neoplasia [15]. CT and MRI findings have not been reported. Calcification in the basal ganglia is seen in many diseases. Among the most common of these are congenital infections, particularly by toxoplasmosis and cytomegalovirus, hypo- and pseudohypoparathyroidism, Fahr's and oculocraniosomatic syndromes, toxic and hypoxic brain damage, mitochondrial cytopathy and postchemotherapeutic changes. Most of these conditions can be excluded
120
Fig.3. Axial T2-weighted MRI (TR/TE = 2500/90) in Cockayne's syndrome. Areas of high intensity in the periventricular white matter (a) and extending into the subcortical U-fibres (b) are clearly seen (arrow). Note enlarged lateral ventricles (a)
Fig.4. Axial CT ataxia telangiectasia. A little calcification is seen in the lentiform nuclei (arrow) and pachygyric changes in the frontal lobes are clearly visible Fig.5. Axial T2-weighted MRI (TR/TE = 2500/90) in ataxia telangiectasia, showing moderate cerebellar atrophy clinically and biochemically. The finding of small calcific foci in our patient with A T adds this condition to the differential diagnosis of basal ganglion calcification. Calcification in basal ganglia was also observed in one patient with an undiagnosed chromosomal instability in whom there was no increased radiosensitivity following exposure of the cells to 100 cGy. However a dicentric chromosome and fragment were observed. This was thought to be a chromosomal instability but CS was exclude& The mechanism of calcification in the brain in D N A repair disorders remains to be elucidated. Few pathological examinations in CS have been reported. "Calcification" in the basal ganglia corresponds to basophilic deposits in vessel walls, containing mainly calcium salts. However,
these "calcified lesions" react strongly with iron stains and only weakly with calcium stains. Basophilic deposits have been seen around neurons and astrocytes containing a brown-black pigment that reacts strongly for melanin and occasionally weakly for iron [16]. It is suggested that these findings explain the M R signal in the basal ganglia of patients with CS. The different patterns of calcification described on MRI probably reflect different states of calcium deposition and the associated high signal intensity on T1-weighted images could be due to an albuminoid matrix binding calcium ions [17]. The white matter lesions are described on histology as having a tigroid pattern with patchy demyelination involving neurons and myelin-forming oligodendroglia [16]. The brain stem may also be involved in this process. In the
121 cerebellum a decrease in the n u m b e r of Purkinje and granular cells has b e e n r e p o r t e d [8, 16]. M R I is m o r e sensitive t h a n C T for imaging these disorders, apart f r o m the detection of calcification. Its specificity is, however, similar. T h e radiological findings in X R A T and F A are nonspecific. In conclusion neuroradiological findings in CS support and can suggest the diagnosis, but are less specific in the o t h e r D N A repair disorders.
References 1. Cockayne EA (1936) Dwarfism with retinal atrophy and deafness. Arch Dis Child 11:14 2. Venema J, Mullenders LH, Natarajan AT, van Zeeland AA, Mayne CV (1990) The genetic defect in Cockayne syndrome is associated with a defect in repair of UV induced DNA damage in transcriptionally active DNA. Proc Natl Acad Sci USA 87: 47074711 3. Timme TL, Moses RE (1988) Diseases with DNA damage processing defects. Am J Med Sci 295:40-48 4. Patton MA, Giannelli F, Francis AJ, Baraitser M, Harding B, Williams AJ (1989) Early onset Cockayne syndrome: case reports with neuropathological and fibroblastic studies. J Med Genet 26:154-159 5. Talwar D, Smith SA (1989) CAMFAK syndrome. Am J Med Genet 34:194-198 6. Levinson P, Zimmerman W, Grammet L, Lewis A, Spackman J (1982) Cockayne syndrome. JCAT 6:1172-1174 7. Dabbagh O, Swaiman KF (1988) Cockayne syndrome: MRI correlation of hypomyelination. Ped Neurol 4:113-116
8. Nishio H, Kodama S, Matsuo T, Ichihashi M, Ito H, Fujiwara Y (1988) Cockayne syndrome: MRI of the brain in a severe form with early onset. J Inherit Metab Dis 11:88-102 9. Boltshauser E, Yalcinkaya C, Wichmann W, Reuter F, Prader A, Valavanis A (1989) MRI in Cockayne syndrome type I. Neuroradiology 31:276-277 10. Demaerel R Wilms G, Verdru R Carton H, Baert AL (1990) MRI in the diagnosis of Cockayne syndrome. J Neuroradiology 17: 157-160 11. Sieg KG, Gaffney GR, McMillan JH (1990) MRI of brain abnormalities in Cockayne syndrome. Kans Med 91:293-294 12. Valk J, van der Knaap MS (1989) MRI in myelin, myelination and myelin disorders. Springer-Verlag pp 149-154 13. Tomimoto H, Hirose S, Akiguchi I, Nishigoori C, Kamemaya M (1989) Xeroderma pigmentosum presenting clinical features of spinocerebellar degeneration. Rinsho Shinkeigaku 29:172-176 14. Mimaki T, Tagawa T, Tanaka J, Sato K, Yabuuchi H (1989) EEG and CT abnormalities in xeroderma pigmentosum. Acta Neurol Scand 80:136-141 15. Bloom D (1954) Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs. Am J Dis Child 88:754-758 16. Softer D, Grotsky HW, Rapin I, Suzuki K (1979) Coekayne syndrome: unusual neuropathological findings and review of the literature. Ann Neurol 6:340-348 17. Araki Y, Furukawa T, Tsuda K, Yamamoto T, Tsukaguchi I (1990) High field MRI of the brain in pseudohypoparathyroidism. Neuroradiology 32:325-327 Dr. P. Demaerel Department of Neuroradiology Hospital for Sick Children Great Ormond Street London UK
