Cockayne syndrome: Review of 25 cases

ELSEVIER Cockayne Syndrome: Review of 25 Cases E m i r e O z d i r i m , M D +, M e r a l T o p q u , M D +, Alev {~zOn, M D * , a n d A y § e n u r Cila, MD* Clinical and laboratory findings of 25 patients with classical Cockayne syndrome (CS) are reviewed. A history of consanguinity was present in 21 patients, and 15 patients had at least 1 affected sibling. Apart from the cardinal features of dwarfism, microcephaly, and mental retardation, the most consistent clinical features included photosensitivity (84%), gait disturbances (84%), progeroid appearance (84%), and ocular abnormalities (88%). The most consistent laboratory findings comprised abnormal nerve conduction (slowed conduction in 13 of the 16 cases with an ENMG), and an abnormal brainstem auditory evoked response (BAER) and/or audiometry (abnormal in 13 of the 17 cases in whom either one of them were available). Cerebral atrophy and calcification of the basal ganglia were the next more common laboratory findings. Clinical criteria are useful in most instances in the diagnosis of CS. In patients in whom the clinical features are controversial for a diagnosis of Cockayne syndrome, studies directed to disorders of myelination involving both peripheral and central nervous systems in conjunction with audiometry may aid in the diagnosis. ©1996 by Elsevier Science Inc. All rights reserved. clinical features in conjunction with laboratory findings that aid in the diagnosis of CS in a clinical setting. Patients and Methods Clinical and Laboratory Findings. Of the 25 cases presented, 14 are male and 11 are female. All patients were admitted with developmental delay except 1 in whom the chief symptom was failure to gain weight. Two patients manifested skin sensitivity on exposure to sunlight, in addition to developmental delay. Twenty-one patients (84%) had a history of consanguinity, and 15 patients had at least 1 affected sibling. The mean age at onset of the symptoms was 2 years (range 10 months to 6 years); and the patients were followed for 10 months to 15 years (mean 5 years). Ozdirim E, Topqu M, Oztn A, Cila A. Cockayne syndrome: review of 25 cases. Pediatr Neurol 1996; 15:312316 Introduction Cockayne syndrome is a rare autosomal recessive disorder characterized by severe postnatal growth retardation and progressive neurologic dysfunction together with other symptoms and signs showing wide variation. Since the first description by Cockayne [1,2], >150 cases have been reported, and different clinical features and characteristic clinical forms are defined in several reviews [3-5]. We report the clinical and laboratory findings of 25 patients diagnosed with classical CS and followed in our institute for the last 15 years and discuss the essential From Departments of *Pediatrics; *Division of Child Neurology, and *Radiology; Ankara, Turkey. 312 PEDIATRIC NEUROLOGY Vol. 15 No. 4 Figure 1. Case 24. A 7-year-old girl with mental retardation, dwarfism (height 92 cm, >3 SD below the mean for age), lipoatrophy, and hyperpigmentation of the skin, skeletal abnormalities, and typical facies. Communications should be addressed to: Dr. Topqu; Department of Pediatrics; Division of Child Neurology; Hacettepe Children's Hospital; 06100, Ankara, Turkey. Received February 12, 1996; accepted June 25, 1996. © 1996 by Elsevier Science Inc. All rights reserved. PII S0887-8994(96)00229-9 • 0887-8994/96/$15.00 Growth failure, microcephaly, delayed psychomotor development, and/or neurologic dysfunction were the constant findings in all cases (Fig 1). Other features occurred with great variability among patients (Table l). More constant findings included photosensitivity (in 21 patients); typical facies with sunken eyes, large beaked nose, and progerioid appearance with loss of subcutaneous fat (in 21 patients), together with large, malformed ears in 9; gait disturbances, mainly ataxic gait (in 15 of the 18 patients who were ambulatory); sensorineural hearing loss (in 10 of the 14 patients in whom audiometry was available and in 3 other patients with abnormal brainstem auditory evoked potentials): and ocular abnormalities in 23 patients (pigmentary retinopathy in 15, optic atrophy in 13, miotic pupiles with decreased response to midriatics in 9, and cataracts in 4). Other features observed relatively less commonly were dental caries (in 14 cases) and skeletal abnormalities. Among the skeletal abnormalities, kyphosis was manifested in 14 patients, ankylosis and joint contractures were evident in 9, 14 had large hands and feet, and 2 manifested pectus excavatus. Congenital dislocation of the hip was present in 2 patients, I of whom actually had arthrogryposis multiplex congenita. Clinodactyly, pes equinovarus, and pectus carinatus were observed in l case each. Laboratory workup in this group of patients included radiological studies, and evaluation of the neurologic function (Table 2). The most common radiotogical findings on direct skull roentgenograms were thickened calvarium and intracranial calcifications, as was reported previously [6]. lntracranial calcifications were observed in 8 of 19 patients in whom direct skull roentgenograms were available. CT scan revealed cerebral atrophy in 14 of 20 patients. Thirteen patients had calcifications in the basal ganglia (Fig 2a). In one case cavum septi pellucidi was present: another case had cerebellar atrophy and mega T a b l e 1, Case cistema magna. Two patients had only mild cerebral atrophy, and CT scan was completely normal in 2. MRI of the brain performed in 5 patients revealed findings suggestive of calcification, especially in the basal ganglia, demyelination of the cerebral white matter, and cortical atrophy in addition to ventricular dilatation, which was attributed to the parenchymal loss (Figs 2b and 3). To assess neurologic function, EEG was performed in 9 patients: cortical dysfunction was detected in 5, one of whom also manifested paroxysmal activity. EEG was normal in the remaining 4. ENMG, performed in 16, revealed slowed nerve conduction velocities in 13: findings were normal in 3. Auditory and visual evoked potentials analyzed in If cases were abnormal in 7. In 3 cases, brainstem auditory evoked responses (BAER) were abnormal when visual evoked potentials (VEP) were normal, and in one instance VEP were abnormal when BAER were normal. Among other laboratory investigations, an abdominal ultrasonography (USG) performed in 12 cases revealed bilateral double collecting systems, left renal nephrocalcinosis, fatty liver with splenomegaly, and hepatomegaly in 1 patient each. USG was normal in the remaining 8 patients. Glucose tolerance test performed in 5 patients was within normal limits in all. Cellular sensitivity to ultraviolet (UV) irradiation had been previously determined autoradiographically in 6 patients 17]: an abnormal post-UV RNA synthesis was demonstrated in all (Fig 4). Discussion CS is a clinically heterogeneous disorder of autosomal recessive inheritance. Cellular hypersensitivily to the le- Clinical features of patients with C o e k a y n e ' s s y n d r o m e Ataxia Ocular Abnormalities* Deafness* Typical Facies Photosensitivity* Kyphosis Large H a n d s and Feet Dental Caries* I + M NA + + + - + 2 3 + + + + + + + + + + + + + + 4 + - + + + - + 5 6 7 8 9 10 11 12 + + + NAm + NAm NAm - + + + -- + + - + + + + -- 4- - + -- 4- 4- 4- 4- 4- - _ 4- - + NA NA + NA + NA NA NA + aBAER + + NA + + aBAER aBAER + + + + + + 13 14 OA, PR, M OA, PR, M OA, PR OA, PR. M OA. PR, M OA, PR PR OA, C, M PR C C, PR C OA M OA, PR, M OA, PR, M PR PR PR OA OA, PR OA 4- 4- 4- -- + + + + 15 16 17 18 19 20 21 22 23 24 25 NAm + + + + + NAm + + NAm NAm - + + + + + + + + + + + + - 4- 4- + + 4- - 4- -- 4- - 4- 4- 4- -- H- + 4- 4- -- -- + + + 4- 4- -- -- _ 4- + 4- 4- 4- * Additional criteria of Cockayne's syndrome according to Nance and Berry [5] in addition to cardinal features of growth failure and neurologic dysfunction are indicated. Abbreviations: + = Present = Absent aBAER = Hearing abnormality as determined by abnormal brainstem auditory evoked response C = Cataract M = Miosis not responding to midriatics NA = Not available NAm = Not ambulatory OA = Optic atrophy PR = Pigmentary retinopathy Ozdirim et al: Cockayne Syndrome 313 Table 2. Case Laboratory features of patients with Cockayne's syndrome Skull X-Ray* Cranial CT CBG-Atrophy t EEG* ENMG ~ VEP BAER 2 +, + A N 3 +, + A N A +, + A N A A 1 -- 4 5 6 7 +, + +, + 8 9 10 11 12 +,+ + + Abdominal USG GTT N N A Bilateral double collecting system A N A N N N N N + +, + N N --, + + +, + - , mild - , mild 13 14 15 Audiometry A A A A N A A A A - , +, Cavum septi N N N A A A A A A A N L renal calcinosis pellucidum 18 + + + +,+ +,+ + A A A 19 20 + + +, + +, + +, Paroxysmal N A A A A N N A A N N A A A A A A 16 17 + N N Fatty liver with splenomegaly N N activity 21 22 23 24 25 Cerebellar atrophy, mega cisterna magna + - +,N N N Hepatomegaly * Intracranial calcification on direct skull X-ray C B G calcification of the basal ganglia on CT-cerebral atrophy * Cortical dysfunction on E E G Nerve conduction velocity on E N M G . Abbreviations: + = Present - = Absent A = Abnormal N = Normal thal effects of UV irradiation was demonstrated in the 1970s by decreased rate of DNA synthesis after exposure to UV with normal unscheduled D N A synthesis and deficient recovery of post-UV RNA synthesis [8-11]. These findings were later attributed to a defect in the preferential repair of transcriptionally active genes; however, the basic pathophysiology of the disease is unknown [7,12,13]. Apart from the universal features of severe growth retardation, microcephaly, and mental retardation, other features are expressed with great variability. This heterogeneous nature of the disorder has been emphasized and attributed to the heterogeneous nature of either the genetic or the underlying biochemical defect in previous small- or large-scale reviews. The cellular sensitivity to sunlight with deficient recovery of RNA synthesis after exposure to UV irradiation provides a useful and sensitive diagnostic tool; however, in many instances, the diagnosis is still based on clinical findings and the efforts to establish the clinical diagnostic criteria are still worthwhile. 314 PEDIATRIC NEUROLOGY Vol. 15 No. 4 Since the first reports by Cockayne, various criteria had been proposed for the clinical diagnosis [1,2,14]. Softer et al. defined major and minor criteria for the diagnosis of CS in 1977 [15]. We now know that photosensitivity, which was classified among the minor criteria by Softer et al. [15], is a strong correlate of the biochemical defect and is not an infrequent finding as reported by Softer et al. Recently, Nance and Berry published a comprehensive review of 140 cases from the literature and proposed their criteria for the clinical diagnosis of CS based on their findings [5]. Twenty-one (84%) of our patients fulfill the clinical criteria of Nance and Berry [5] (Table 1). Three of the remaining 4 patients were siblings, all of whom manifested cataracts, demyelinating neuropathy, and hypogonadism in addition to the cardinal features. Other findings in 2 of the siblings included pigmentary retinopathy in 1, and basal ganglia calcifications in the other. The fourth patient had 1 sibling with signs and symptoms typical of CS. A B Figure 2. Case 20. An 18-year-old boy. (a) CT reveals thickened skull, overt cerebral atrophy, and bilateral pallidal calcifications with hypodense white matter in both frontal lobes. (b) Coronal T/-weighted SE MRI (TR." 480 ms, TE." 25 ms) shows bilateral hyperintensities of globus pallidi and diffuse cerebral atrophy. None of the 25 cases we report manifested the earlyonset severe form of CS as described by Lowry [16]. Photosensitivity, ocular abnormalities, and typical stance with progeroid facies were equally common in the present series. Sensorineural hearing loss was relatively less common, but we attribute this to difficulties in accomplishing an audiometric study in our patients. Such a study is valuable, however, if it produces a high yield of abnormal findings. Among the clinical correlates of a positive diagnosis as reported by Lehmann et al. [7], those most common in the present series were photosensitivity and gait disturbances, pigmentary retinopathy and dental caries were relatively less common. In view of the findings in our group of patients, the diagnostic criteria suggested by Nance and Berry are obviously valuable in the clinical diagnosis of most if not all patients with CS. In patients in whom the clinical features are inadequate for the diagnosis of CS, further evaluation of the neurologic function with studies especially assessing specific areas of both central and peripheral nervous systems (CT, MRI, ENMG, audiometry, BAER) should be performed clinically when cellular diagnosis is not possible. Parental consanguinity has been reported previously, and many patients had affected siblings, suggesting an autosomal recessive pattern in CS. High frequency of parental consanguinity as well as a history of at least 1 affected sib in more than half of the cases in our series strongly supports the autosomal recessive pattern of inheritance. In only one instance were both affected siblings male, but the parents were consanguineous. Because both affected siblings in another family are female, the affected brothers are believed to be a coincidence rather than an example of X-linked inheritance. The high frequency of parental consanguinity in the present series is attributed to the high frequency of inbred marriages in our country [ 17], 120 A 100 -.-- Case 5 -,.--- Case 6 '2 Case 15 80 -o-- Case 16 g .~ Case 19 Case 20 60 ' -e-- Normal 8 ~" 4o z¢Y 20 c 0 I I I 5 10 15 u v dose (Jrn 2) Figure 3. Case 5. An 8-year-old boy. T2-Weighted SE transverse image (TR: 2,600 ms, TE: 100 ms) shows loss of white matter and myelin in symmetric Jashion; U-fibers are also involved. Ventricles are dilated secondary to tile cerebral parenchymal loss. Figure 4. Post-ultraviolet RNA synthesis as determined by autoradiography in 6 patients with Cockayne's syndrome. Data were ,from at least two experiments in each case. O z d i r i m et al: C o c k a y n e Syndrome 315 which also explains the large number of cases in our series as compared with those in other centers. This work was supported by the Turkish Child Neurology Association. We thank Professor A. R. Lehmann of MRC Cell Mutation Unit, University of Sussex, for analysis and for providing the post-UV RNA synthesis data on our patients. References [1] Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1936; 11:1-8. [2] Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1946;21:52-4. [3] KiHong J, Handa T, Ishibara T, Yoshii F. Cockayne's syndrome: report of two siblings and review of the literature. Jpn Brain Dev 1979; 1:305-12. [4] Cantani A, Bamonte G, Bellioni P. Rare syndromes i. Cockayne syndrome: a review of the 129 cases so far reported in the literature. Eur Rev Med Pharrn Sci 1987;9:9-17. [5] Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet 1992;42:68-84. [6] Alton DJ, McDonald P, Reilly BJ. Cockayne's syndrome: a report of three cases. Radiology 1972;102:403-6. [7] Lehmann AR, Thompson AF, Harcourt SA, Stefanini M, Norris PG. Cockayne Syndrome: correlation of clinical features with cellular sensitivity of RNA synthesis to UV irradiation. J Med Genet 1993;30: 679-82. 316 PEDIATRIC NEUROLOGY Vol. 15 No. 4 [8] Schmickel RD, Chu EHY, Trosko JE. The definition of a cellular defect in two patients with CS. Pediatr Res 1975;9:317. [9] Andrews AD, Barrett SF, Yoder FW, Robbins JH. Cockayne's syndrome fibroblasts have increased sensitivity to ultraviolet light but normal rates of unscheduled DNA synthesis. J Invest Dermatol 1978;70: 237-9. [10] Sehmickel RD, Chu EHY, Trosko JE, Chang CC. Cockayne's syndrome, a cellular hypersensitivity to ultraviolet light. Pediatrics 1977; 60:135-9. [11] Mayne LV, Lehmann AR. Failure of RNA synthesis to recover after UV irradiation: an early defect in cells from individuals with Cockayne's syndrome and xeroderma pigmentosum. Cancer Res 1982;42: 1473-8. [12] Mellon I, Bohr VA, Smith CA, Hanawalt PC. Preferential DNA repair of an active gene in human cells. Proc Natl Acad Sci USA 1986; 83:8878-82. [13] Venema J, Mullenders LHF, Natarajan AT, Van Zeeland AA, Mayne LV. The genetic defect in CS is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA. Proc Natt Acad Sci USA 1990;87:4707-11. [14] Neill CA, Dingwall MM. A syndrome resembling progeria: a review of two cases. Arch Dis Child 1950;25:213-21. [15] Softer D, Grotsky H, Rapin I, Suzuki K. Cockayne's syndrome: unusual neuropathotogic findings and review of the literature. Ann Neurol 1979;6:340-8. [16] Lowry RB. Early onset of Cockayne syndrome. Am J Med Genet 1982; 13:209-10. [17] Tunqbilek E, Ko~ 1. Consanguineous marriage in Turkey and its impact on fertility and mortality. Ann Hum Genet 1994;58:321-9.