CASE REPORT
Cockayne Syndrome: Report of Two Siblings and Review of Literature in Japan KiHong Jin, MD, Teruhiko Handa, MD, Tadayuki Ishihara, MD, Fumihito Yoshii, MD
Typical Cockayne syndrome was seen in a boy and his younger sister and these two cases are reported here, and reported cases of the syndrome in Japan are summarized. Both cases (an 11-year-old boy and a 7-year-old girl) had dwarfism, a senile face, retinitis pigmentosa._ photosensitivity, and mental retardation. Calcium deposition in the basal ganglia was seen by CT scan. In both cases nerve conduction velocities were reduced suggesting peripheral neuropathy, but segmental demyelination on sural nerve biopsy was not demonstrated. Twenty seven cases of the syndrome has now been reported in Japan in 21 families (including the above two cases), consisting of 14 males and 12 females (the sex of one case was unknown): consanguineous marriage was confirmed in 14 families. Eleven cases in five families were siblings. The estimated ages of onset were from 1 month to 3 years, and in most cases photosensitivity was the initial symptom. Clinical manifestations were mental retardation in 25 cases (93%), dwarfism in 24 cases (89%), photosensitivity in 23 cases (85%), articular contracture in 22 cases (81%), sunken eyes in 20 cases (74%), retinitis pigmentosa in 17 cases (63%), deafness in 16 cases (59%), and intracranial calcification in 14 cases (51%). Intracranial calcification will be more often detected in future following the development of CT scanning. Jin K, Handa T, Ishihara T, Yoshii F: Cockayne syndrome: Report of two siblings and review of literature in Japan. Brain Dev 4: 305-312, 1979.
Cockayne [4], an English pediatrician, encountered a girl and her younger btother showing senile facial characteristics with sunken eyes and prognathism, mental retardation, retinitis
pigmentosa, hearing impairment, and photosensitive dermatitis. He considered the cases to be examples of a new syndrome, which he reported under the title of "dwarfism with retinal atrophy and deafness" in 1936. After 10 years he [5] reported their progress. In 1950 Neill From Departments of Pediatrics (KJ, TH) and Internal [22] reported two brothers with similar sympMedicine (TI), Higashi Saitama National Hospital, toms, together with tremor, intracranial calcifiSaitama, Department of Neurology (FY), Tokai Unication, resistance to mydriatics and hepatospleversity, School of Medicine, Kanagawa. nomegaly which were observed for the first Received for pUblication: July 13, 1979. time. In Japan 25 cases of the syndrome from Accepted for publication: October 3, 1979. 20 families have previously been reported. The Key words: Cockayne syndrome, CT scan, intracranial calcification, peripheral neuropathy, sural authors encountered a boy and his younger nerve biopsy. sister who were assumed to have the syndrome, Correspondence address: Dr. KiHong Jin, Department and reviewed and discussed the previously reof Pediatrics, Jikei University School of Medicine, ported cases of the syndrome in Japan. The 3-19-18, Nishishinbashi, Minato-ku, Tokyo 105, Japan. results are reported hereinafter.
Fig 1 Case 1 (a) and Case
2 (b) showing senile face, short trunk and long extremities.
(a)
Case Reports
Case 1
The patient was an ll-year-old boy with chief complaint of retardation and subsequent regression of mental and motor development. His parents are cousins. Two of the siblings (Cases 1 and 2) show the syndrome but the others are normal. He was delivered by cesarean section due to a narrow pelvis after a gestation of 43 weeks; the birth weight was 3,1 00 g. He showed no abnormal symptoms in the neonatal period. No particular symptom has been observed except that erythema appears frequently in spring and summer. From 3 months after birth, retardation of the body weight increase was noted; the head set steadily at 6 months after birth; he turned over at 8 months, sat up at 10 mdnths, and began to walk with 2 or 3 steps at 2 years of age; then he could not run or go up and down stairs. He showed regression in development from 5 years of age; walking became difficult for him and he could not walk at 9 years of age; he became unskillful in manipulating his fingers, and could hardly use a spoon. He could say "papa" and "mama" at 3 years of age and 306 Brain & Development, Vall, No 4,1979
(b)
then gradually more words, but from 5 years of age his speaking ability began to deteriorate, and now he can say only a few meaningful words. On physical examination, he is very small and shows cachectic dwarfism (Fanconi index, 55%): height 113 cm, weight 16.8 kg, head circumference 47.5 cm and rather long limbs for the height. The appearance of his face is senile with a thin subcutaneous fat layer, sunken eyes, a high nose, and a projected maxilla. His teeth are all carious, and he has kyphosis, both thumbs bending inward and both thenar eminences being atrophied; the second toes overlap the first ones, and he has talipes equinovarus, clawfoot, and shortening of adductor muscles of the thigh. The abdomen, chest and heart are normal. On walking with support, he lifts the knee high, and puts the foot on the floor tip first. The deep tendon reflexes are normal, but Babinski and Rossolimo reflexes are present. Ataxia, dysmetria, tremor, involuntary movement or nystagmus are not seen, but there is slight to moderate deafness. He can say only "mama," "ohi" and "baka." Optic fundi show optic atrophy and retinitis pigmentosa.
Fig 2 CT scan findings. Dila ta tion of ven tricles and calcification in the corpus striatum and the internal capsule are seen in Case I (a) and Case 2(b). In Case I (a), calcification is also seen in the frontal lobe. The calcified sites were not enhanced after infusion of contrast medium.
(aj
(b)
General amyotrophy is seen, and it is particularly marked in the distal parts. His limbs are cold. DQ is 31. Laboratory findings: WBC, CRP, and the serum protein are normal; the erythrocyte sedimentation rate is accelerated moderately; in the spinal fluid, the cell count is 2/mm 3 and the protein is increased to lOOmg/dl. General urinary tests are normal. T 3, 105 ng/dl; T 4, 1O.2J.Lg/dl; TSH, 2-6J.Lu/ml; HGH, 5.2ng/ml; insulin, 1Q J.Lu/ml; they are all in the normal ranges, 170HCS, 1.7mg/day (4.7±2.l) and 17 KS, 1.1 mg/day (0.24-1.44); the former is low. Analysis of urine and serum amino acids by paper chromatography is normal. Arylsulfatase A activity is normal. Cranial X-ray findings: A thick calvarium and calcification are seen. CT scan. A moderate enlargement of the ventricles and calcification in the corpus striatum and the frontal lobe are recognized. No enhancement is seen after intravenous injection of Couray. Motor conduction velocity of the right median nerve is reduced to 30.S m/sec, but no abnormal findings are obtained in sural nerve biopsy material (Fig 3). A tendency toward type II fiber predominance is seen in a biopsy from the biceps brachii muscle (Fig 4). Case 2 The patient was a 7-year-old girl with chief complaint of retardation and subsequent regression of mental and motor development. She was delivered after a 41-week gestation; the birth weight was 2,SOO g. Erythema ap-
peared in spring and summer. The head set steadily at 5 months after birth; she turned over at 7 months; she began to walk at IS months anp could go up and down stairs, but from 5 years of age she was apt to fall down and now she can walk only several steps. She could say "papa" and "mama" at 3 years of age, and now she can say individual words but cannot say 2-word sentences. Since IS months retardation of the body weight increase has been noted. On physical examination, she is very small and shows dwarfism (Fanconi index, 43%): height 94 cm, weight 11.S kg, head circumference 45 cm, and rather long limbs for the height. The appearance of her face is senile, similar to her brother's. The abdomen, chest and heart are normal. She shows contracture of the foot joint (talipes equinus), shortening of adductor muscles of the thigh, and amyotrophy of the distal parts of limbs; the deep tendon reflexes are normal, but the Rossolimo reflex is present. Hearing is bad and nystagmus is absent. Dysmetria, tremor, asynergy, ataxia or involuntary movement are not seen. Her limbs are cold. Optic fundi show optic atrophy and retinitis pigmentosa. Laboratory findings: The results of examinations are similar to those of her brother: the erythrocyte sedimentation rate is moderately accelerated; the protein in the spinal fluid is increased to 75 mg/dl; 170HCS is 0.6 mg/day (2.9±0.SS) and 17KS is O.4mg/day (0.562.42); they are low. The other hematological and urinary test results are all in the normal lin, et al: Cockayne syndrome 307
Fig 3 Sural nerve biopsy from Case 1 showing no abnormal findings. (Electron microscopy, x
6,600)
Fig 4 Biceps brachial muscle biopsy from Case 1 showing the tendency to type II fiber predominance. (Regular ATPase, x 40)
308 Brain & Development, Vol 1, No 4,1979
Table I Laboratory findings Case 2
Case 1 RBC Hb (g/dl) Ht (%) WBC Platelet ESR (lhr) CRP GOT (U) GPT (U) LDH (U)
Alk. P. (U) CPK (IU) Aldolase (IU) Blood sugar (mg/dl)
395 x 10 12.6
4
13.0
37 7,700 48 .2 x 10
411xl04
38 8,800 4
25
40.8 x 10 23
(- )
(- )
29 36 298 27.4
30
65 3.9 93
32 380 18.2 39 5.0 84
T. cholesterol (mg/dl) Na (mEq/L) K (ditto)
184 144 4 .6
194 143
CI ( ditto) Ca ( ditto) P (ditto)
110
1\0
TPHA T. Protein (g/d!) Alb (%)
(3
(%) (%) (%)
'Y
(%)
at a2
S-Cu (/lg/dl) S-ceruloplasmin (mg/dl) T3 (ng/dl) T4 (/lg/dl) TSH (/lU/dl) HGH (ng/ml) Parathormone (ng/ml) Insulin ().IU/ml) Urinalysis Urine-l 7 OHCS (mg/day) Urine-17KS (mg/day) CSF CC Protein (mg/dl) Sugar (mg/dl) ECG EEG MCV of rt median nerve (m/sec)
5.5 4 .1
(-) 7.2 53.5 4.9 9.8 11.9 19 .6 107 35
!O5 10.2 2.6 5.2 0.23 19 Normal 1.7 1.1
3 l/mm 100 60 Normal Normal 30.8
4.5 4.8 4.5 (- )
7.0 60.8 5.0 11.2 8.4 14.3 118 38 136 9.7 2.6 5.7 0.1 4
Normal 0.6 0.8 3
l/mm 75 50 Normal Normal 27
4
ranges. Arylsulfatase A activity is normal. Analysis of amino acids is normal. Cranial X-ray examination: A thick calvarium is seen but calcification is not found. CT scan: Enlargement of the ventricles and calcification of the corpus striatum are seen. No change is found after intravenous injection ofConray. Motor conduction velocity of the right median nerve is reduced to 27.0 mg/sec. EEG is normal. In sural nerve biopsy material abnormal findings such as segmental demyelination are not obtained (electron microscopy, optical microscopy). Her parents' CT scan findings are normal. Discussion The authors reviewed the literature and found 25 cases of the syndrome in 20 families in Japan [16,17,21 , 26,28-31]; thus, the total of the cases is 27 cases in 21 families , including the two cases reported above. They consist of 14 males an d 12 females (one case is of unknown sex) and no significant difference is seen between the sexes. According to Rawlatt [27] 28 cases were reported in Europe and America up to 1969, consisting of 21 males and 7 females; the difference between the sexes is large. In the 21 Japanese families, consanguineous marriage was found in 14 families (There were no description in five families). The syndrome appears in siblings, in 11 cases from five families. Autosomal recessive inheritance is suggested. The initial symptom is photosensitivity in most cases. The estimated age of onset is from 3 months to 3 years of age. As to the clinical manifestations, retardation of mental development was seen in 25 cases (93%), dwarfism in 24 cases (89%), photosensitivity in 23 cases (85%); articular contracture in 22 cases· (81 %), dep(essed eyeballs in 20 cases (74%), retinitis pigmentosa in 17 cases (63%), deafness in 16 cases (59%), ataxia or dysbasia in 15 cases (56%), intracranial calcification in 14 cases (51%), tremor in 13 cases (48%), optic atrophy in 11 cases (40%), dysfunction of kidneys in seven cases (26%), peripheral neuropathy in siX. cases (22%), and appearance of pathological reflexes in six cases (22%). The present cases show dwarfism, microcephaly, senile appearance of the face, retardation of mental development, photosensitivity, lin, et al: Cockayne syndrome 309
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Cockayne Syndrome: Report of Two Siblings and Review of Literature in Japan KiHong Jin, MD, Teruhiko Handa, MD, Tadayuki Ishihara, MD, Fumihito Yoshii, MD
Typical Cockayne syndrome was seen in a boy and his younger sister and these two cases are reported here, and reported cases of the syndrome in Japan are summarized. Both cases (an 11-year-old boy and a 7-year-old girl) had dwarfism, a senile face, retinitis pigmentosa._ photosensitivity, and mental retardation. Calcium deposition in the basal ganglia was seen by CT scan. In both cases nerve conduction velocities were reduced suggesting peripheral neuropathy, but segmental demyelination on sural nerve biopsy was not demonstrated. Twenty seven cases of the syndrome has now been reported in Japan in 21 families (including the above two cases), consisting of 14 males and 12 females (the sex of one case was unknown): consanguineous marriage was confirmed in 14 families. Eleven cases in five families were siblings. The estimated ages of onset were from 1 month to 3 years, and in most cases photosensitivity was the initial symptom. Clinical manifestations were mental retardation in 25 cases (93%), dwarfism in 24 cases (89%), photosensitivity in 23 cases (85%), articular contracture in 22 cases (81%), sunken eyes in 20 cases (74%), retinitis pigmentosa in 17 cases (63%), deafness in 16 cases (59%), and intracranial calcification in 14 cases (51%). Intracranial calcification will be more often detected in future following the development of CT scanning. Jin K, Handa T, Ishihara T, Yoshii F: Cockayne syndrome: Report of two siblings and review of literature in Japan. Brain Dev 4: 305-312, 1979.
Cockayne [4], an English pediatrician, encountered a girl and her younger btother showing senile facial characteristics with sunken eyes and prognathism, mental retardation, retinitis
pigmentosa, hearing impairment, and photosensitive dermatitis. He considered the cases to be examples of a new syndrome, which he reported under the title of "dwarfism with retinal atrophy and deafness" in 1936. After 10 years he [5] reported their progress. In 1950 Neill From Departments of Pediatrics (KJ, TH) and Internal [22] reported two brothers with similar sympMedicine (TI), Higashi Saitama National Hospital, toms, together with tremor, intracranial calcifiSaitama, Department of Neurology (FY), Tokai Unication, resistance to mydriatics and hepatospleversity, School of Medicine, Kanagawa. nomegaly which were observed for the first Received for pUblication: July 13, 1979. time. In Japan 25 cases of the syndrome from Accepted for publication: October 3, 1979. 20 families have previously been reported. The Key words: Cockayne syndrome, CT scan, intracranial calcification, peripheral neuropathy, sural authors encountered a boy and his younger nerve biopsy. sister who were assumed to have the syndrome, Correspondence address: Dr. KiHong Jin, Department and reviewed and discussed the previously reof Pediatrics, Jikei University School of Medicine, ported cases of the syndrome in Japan. The 3-19-18, Nishishinbashi, Minato-ku, Tokyo 105, Japan. results are reported hereinafter.
Fig 1 Case 1 (a) and Case
2 (b) showing senile face, short trunk and long extremities.
(a)
Case Reports
Case 1
The patient was an ll-year-old boy with chief complaint of retardation and subsequent regression of mental and motor development. His parents are cousins. Two of the siblings (Cases 1 and 2) show the syndrome but the others are normal. He was delivered by cesarean section due to a narrow pelvis after a gestation of 43 weeks; the birth weight was 3,1 00 g. He showed no abnormal symptoms in the neonatal period. No particular symptom has been observed except that erythema appears frequently in spring and summer. From 3 months after birth, retardation of the body weight increase was noted; the head set steadily at 6 months after birth; he turned over at 8 months, sat up at 10 mdnths, and began to walk with 2 or 3 steps at 2 years of age; then he could not run or go up and down stairs. He showed regression in development from 5 years of age; walking became difficult for him and he could not walk at 9 years of age; he became unskillful in manipulating his fingers, and could hardly use a spoon. He could say "papa" and "mama" at 3 years of age and 306 Brain & Development, Vall, No 4,1979
(b)
then gradually more words, but from 5 years of age his speaking ability began to deteriorate, and now he can say only a few meaningful words. On physical examination, he is very small and shows cachectic dwarfism (Fanconi index, 55%): height 113 cm, weight 16.8 kg, head circumference 47.5 cm and rather long limbs for the height. The appearance of his face is senile with a thin subcutaneous fat layer, sunken eyes, a high nose, and a projected maxilla. His teeth are all carious, and he has kyphosis, both thumbs bending inward and both thenar eminences being atrophied; the second toes overlap the first ones, and he has talipes equinovarus, clawfoot, and shortening of adductor muscles of the thigh. The abdomen, chest and heart are normal. On walking with support, he lifts the knee high, and puts the foot on the floor tip first. The deep tendon reflexes are normal, but Babinski and Rossolimo reflexes are present. Ataxia, dysmetria, tremor, involuntary movement or nystagmus are not seen, but there is slight to moderate deafness. He can say only "mama," "ohi" and "baka." Optic fundi show optic atrophy and retinitis pigmentosa.
Fig 2 CT scan findings. Dila ta tion of ven tricles and calcification in the corpus striatum and the internal capsule are seen in Case I (a) and Case 2(b). In Case I (a), calcification is also seen in the frontal lobe. The calcified sites were not enhanced after infusion of contrast medium.
(aj
(b)
General amyotrophy is seen, and it is particularly marked in the distal parts. His limbs are cold. DQ is 31. Laboratory findings: WBC, CRP, and the serum protein are normal; the erythrocyte sedimentation rate is accelerated moderately; in the spinal fluid, the cell count is 2/mm 3 and the protein is increased to lOOmg/dl. General urinary tests are normal. T 3, 105 ng/dl; T 4, 1O.2J.Lg/dl; TSH, 2-6J.Lu/ml; HGH, 5.2ng/ml; insulin, 1Q J.Lu/ml; they are all in the normal ranges, 170HCS, 1.7mg/day (4.7±2.l) and 17 KS, 1.1 mg/day (0.24-1.44); the former is low. Analysis of urine and serum amino acids by paper chromatography is normal. Arylsulfatase A activity is normal. Cranial X-ray findings: A thick calvarium and calcification are seen. CT scan. A moderate enlargement of the ventricles and calcification in the corpus striatum and the frontal lobe are recognized. No enhancement is seen after intravenous injection of Couray. Motor conduction velocity of the right median nerve is reduced to 30.S m/sec, but no abnormal findings are obtained in sural nerve biopsy material (Fig 3). A tendency toward type II fiber predominance is seen in a biopsy from the biceps brachii muscle (Fig 4). Case 2 The patient was a 7-year-old girl with chief complaint of retardation and subsequent regression of mental and motor development. She was delivered after a 41-week gestation; the birth weight was 2,SOO g. Erythema ap-
peared in spring and summer. The head set steadily at 5 months after birth; she turned over at 7 months; she began to walk at IS months anp could go up and down stairs, but from 5 years of age she was apt to fall down and now she can walk only several steps. She could say "papa" and "mama" at 3 years of age, and now she can say individual words but cannot say 2-word sentences. Since IS months retardation of the body weight increase has been noted. On physical examination, she is very small and shows dwarfism (Fanconi index, 43%): height 94 cm, weight 11.S kg, head circumference 45 cm, and rather long limbs for the height. The appearance of her face is senile, similar to her brother's. The abdomen, chest and heart are normal. She shows contracture of the foot joint (talipes equinus), shortening of adductor muscles of the thigh, and amyotrophy of the distal parts of limbs; the deep tendon reflexes are normal, but the Rossolimo reflex is present. Hearing is bad and nystagmus is absent. Dysmetria, tremor, asynergy, ataxia or involuntary movement are not seen. Her limbs are cold. Optic fundi show optic atrophy and retinitis pigmentosa. Laboratory findings: The results of examinations are similar to those of her brother: the erythrocyte sedimentation rate is moderately accelerated; the protein in the spinal fluid is increased to 75 mg/dl; 170HCS is 0.6 mg/day (2.9±0.SS) and 17KS is O.4mg/day (0.562.42); they are low. The other hematological and urinary test results are all in the normal lin, et al: Cockayne syndrome 307
Fig 3 Sural nerve biopsy from Case 1 showing no abnormal findings. (Electron microscopy, x
6,600)
Fig 4 Biceps brachial muscle biopsy from Case 1 showing the tendency to type II fiber predominance. (Regular ATPase, x 40)
308 Brain & Development, Vol 1, No 4,1979
Table I Laboratory findings Case 2
Case 1 RBC Hb (g/dl) Ht (%) WBC Platelet ESR (lhr) CRP GOT (U) GPT (U) LDH (U)
Alk. P. (U) CPK (IU) Aldolase (IU) Blood sugar (mg/dl)
395 x 10 12.6
4
13.0
37 7,700 48 .2 x 10
411xl04
38 8,800 4
25
40.8 x 10 23
(- )
(- )
29 36 298 27.4
30
65 3.9 93
32 380 18.2 39 5.0 84
T. cholesterol (mg/dl) Na (mEq/L) K (ditto)
184 144 4 .6
194 143
CI ( ditto) Ca ( ditto) P (ditto)
110
1\0
TPHA T. Protein (g/d!) Alb (%)
(3
(%) (%) (%)
'Y
(%)
at a2
S-Cu (/lg/dl) S-ceruloplasmin (mg/dl) T3 (ng/dl) T4 (/lg/dl) TSH (/lU/dl) HGH (ng/ml) Parathormone (ng/ml) Insulin ().IU/ml) Urinalysis Urine-l 7 OHCS (mg/day) Urine-17KS (mg/day) CSF CC Protein (mg/dl) Sugar (mg/dl) ECG EEG MCV of rt median nerve (m/sec)
5.5 4 .1
(-) 7.2 53.5 4.9 9.8 11.9 19 .6 107 35
!O5 10.2 2.6 5.2 0.23 19 Normal 1.7 1.1
3 l/mm 100 60 Normal Normal 30.8
4.5 4.8 4.5 (- )
7.0 60.8 5.0 11.2 8.4 14.3 118 38 136 9.7 2.6 5.7 0.1 4
Normal 0.6 0.8 3
l/mm 75 50 Normal Normal 27
4
ranges. Arylsulfatase A activity is normal. Analysis of amino acids is normal. Cranial X-ray examination: A thick calvarium is seen but calcification is not found. CT scan: Enlargement of the ventricles and calcification of the corpus striatum are seen. No change is found after intravenous injection ofConray. Motor conduction velocity of the right median nerve is reduced to 27.0 mg/sec. EEG is normal. In sural nerve biopsy material abnormal findings such as segmental demyelination are not obtained (electron microscopy, optical microscopy). Her parents' CT scan findings are normal. Discussion The authors reviewed the literature and found 25 cases of the syndrome in 20 families in Japan [16,17,21 , 26,28-31]; thus, the total of the cases is 27 cases in 21 families , including the two cases reported above. They consist of 14 males an d 12 females (one case is of unknown sex) and no significant difference is seen between the sexes. According to Rawlatt [27] 28 cases were reported in Europe and America up to 1969, consisting of 21 males and 7 females; the difference between the sexes is large. In the 21 Japanese families, consanguineous marriage was found in 14 families (There were no description in five families). The syndrome appears in siblings, in 11 cases from five families. Autosomal recessive inheritance is suggested. The initial symptom is photosensitivity in most cases. The estimated age of onset is from 3 months to 3 years of age. As to the clinical manifestations, retardation of mental development was seen in 25 cases (93%), dwarfism in 24 cases (89%), photosensitivity in 23 cases (85%); articular contracture in 22 cases· (81 %), dep(essed eyeballs in 20 cases (74%), retinitis pigmentosa in 17 cases (63%), deafness in 16 cases (59%), ataxia or dysbasia in 15 cases (56%), intracranial calcification in 14 cases (51%), tremor in 13 cases (48%), optic atrophy in 11 cases (40%), dysfunction of kidneys in seven cases (26%), peripheral neuropathy in siX. cases (22%), and appearance of pathological reflexes in six cases (22%). The present cases show dwarfism, microcephaly, senile appearance of the face, retardation of mental development, photosensitivity, lin, et al: Cockayne syndrome 309
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