American Journal of Medical Genetics 42:68-84 (1992)
Cockayne Syndrome: Review of 140 Cases -
Martha A. Nance and Susan A. Berry Department of Pediatrics (M.A.N., S.A.B.) and Institute of H u m a n Genetics (S.A.B.), University of Minnesota, Minneapolis To define diagnostic criteria for Cockayne Syndrome (CS) and to identify in detail the complications of the condition, a comprehensive review of 140 cases of CS was performed. Criteria required for the diagnosis include poor growth and neurologic abnormality; other very common manifestations include sensorineural hearing loss, cataracts, p i g mentary retinopathy, cutaneous photosensitivity, and dental caries. The mean age of death in reported cases is 123112 years, though a few affected individuals have lived into their late teens and twenties. Prenatal growth failure, congenital structural eye anomalies, severe neurologic dysfunction from birth, and the presence of cataracts within the first 3 years of life are predictors of severe disease and early death. In contrast with other disorders of chromosome or DNA repair, cancer has never been reported in a classical CS patient, and there appears to be no predisposition to infectious complications. The wide spectrum of symptoms and severity of the disease suggest that biochemical and genetic heterogeneity exist. CS is an uncommon but devastating genetic condition which will be better understood as the biochemical interrelationships between DNA replication and repair, and between growth, homeostasis, and oncogenesis are unraveled.
INTRODUCTION Cockayne Syndrome (CS) is a rare autosomal recessive disorder of unknown pathogenesis which results in postnatal growth failure and progressive neurologic dysfunction, along with a host of other clinical symptoms and signs. Since the first report of this condition by Cockayne in 1936 [16], over 150 cases have been reported, but there has not previously been a comprehensive review of all the manifestations of the syndrome. The most extensive previous reviews are those of Cantani et al. 1121, Guzzetta [38], Houston [45],and Nyhan [87]. We present here 5 additional cases of CS, review previously reported cases, define the characteristic clinical forms of the condition, discuss atypical cases, and comment on the importance of using biochemical assays of nucleic acid metabolism to help define and diagnose the condition. The intent of this review is to serve as a resource for physicians and other caregivers of CS patients regarding the important characteristics of the syndrome, and to identify which manifestations are of particular significance in the long term prognosis of patients with the condition.
CLINICAL REPORTS Patient 1 (Fig. 1) was reported in 1976 as a case of tryptophanuria [1371. He carried that diagnosis until 1988, when, a t the age of 21, he was admitted to the University of Minnesota with acute and chronic behavior changes. At that time he had the obvious physical stigmata of CS (Fig. 1, lower right panel). He had a weight of 26.8 kg, height of 115.5 cm, head circumKEY WORDS: leukodystrophy, DNA repair, ference (OFC)of 51 cm., anhidrosis and a dry scaly rash growth failure, pigmentary over sun-exposed areas. Ophthalmologic examination retinopathy, cataracts, senshowed dry eyes, miotic pupils, a mild exotropia, mild sorineural deafness, caries, pigmentary retinopathy, optic atrophy, and hyperopia. autosomal recessive inheriHe had previously had multiple procedures for dental tance caries. Blood pressure was 106/60, and results of examination of heart and lungs were unremarkable. There was moderate hepatomegaly without splenomegaly, accompanied by chronic mild elevation of serum liver enzyme levels (SGOT 59 I.U.11, SGPT 118 I.U./l; normal range 0-50). He had intermittent diarrhea and proctalgia fugax. Secondary sexual characteristics were Received for publication February 8,1991; revision received May present. Neurologic exam showed well-developed mus16, 1991. Address reprint requests to Martha A. Nance, M.D., Depart- culature with normal strength. The intelligence quoment of Neurology-823, Hennepin County Medical Center, 701 tient (IQ) was estimated a t 30, though the patient’s social level of functioning was greater than evidenced on Park Avenue South, Minneapolis, Minnesota 55415. 0 1992 Wiley-Liss, Inc.
Cockayne Syndrome
Fig. 1. Patient 1at age 1(upper left panel), age 3 (upper right),age 9 (lower left), and age 21 (lower right). The appearance is normal a t age 1; at age 3, short stature, mild cutaneous erythema and an abnormal posture are evident; by age 9, a scaly, peeling photodermatitis is prominent, as are relatively normal-sized teeth set in a small mouth. At age 21, the face is drawn and thin, the eyes sunken, and the posture stooped due to kyphosis and flexion contractures a t the hips, knees, and ankles.
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70
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formal intelligence testing. His voice had a highpitched, nasal, and mildly dysarthric quality. He had a spastic-ataxic gait; reflexes in the lower limbs were brisk and plantar responses were upgoing. An electroencephalogram (EEG) was abnormal, due to mild generalized slowing; magnetic resonance imaging (MRI) and computerized tomography (CT) scans of the brain showed a thickened cranial vault, cerebral atrophy, basal ganglia calcifications, and increased T2 signal in the superior periventricular regions bilaterally. Audiometry showed a flat 65 dB pure-tone loss from 0.5-4.0 kHz bilaterally, with slightly better speech discrimination. Qmpanograms were normal. Blood urea nitrogen (BUN) and creatinine were normal. Studies of fibroblasts showed a 37%ultraviolet (UV) survival dose of 3.0 Jouledmeter, with a normal control of 21.0 J/m; excision repair was 82%of normal. Based on the laboratory and clinical findings, the diagnosis of CS was made. He has been followed since that time for increasing gait spasticity, hearing loss, and behavior problems. Patient 2 (Fig. 2) was evaluated a t the age of lil/iz years for growth failure. She had a birthweight of 2,400 g and length of 48 cm after an uneventful pregnancy. She was gavage-fed for two months because of poor feeding. A cleft soft palate repair was performed at 10 months. Tympanostomy tubes were placed at 18 months because of recurrent otitis media and upper respiratory infections.When endocrine,gastrointestinal, and chromosome evaluation did not uncover a cause for her poor
growth (6.95 kg, 77.7 cm at lll/iz years), she was referred for evaluation. She had entirely normal eye findings; fine dry hair; mild photosensitivity; no abnormalities of heart, lungs, or abdomen; mild developmental delay; and a stooped standing posture (Fig. 2). She made noises, but no specific words, and could take only 1-2 steps. Neurologic abnormalities were more definite a t 28 months, when she had increased tone and reflexes in the lower extremities; an unsteady, wide-based gait; and mild dysmetria. Her bone age was delayed (9 months at chronological age 18 months), and an MRI scan showed questionable areas of increased T2 signal in the periventricular regions. Her fibroblasts showed at 37%UV survival dose of 4.5 J/m, with a pooled normal control dose of 17.4 Jlm; DNA repair as assayed by thymidine dimer excision was 66.2%of normal. Three additional cases have been reported from our institution [26,128], and the clinical data from these individuals were incorporated into this review. Patients 3 and 4 were sibs who were evaluated in 1988 when they were admitted for gastrostomy tube placement. In 1990, at the age of 6 years, patient 3 weighed 17.2 kg and had a height of 101 cm; his sister (age 5 years) weighed 17.5 kg and had attained 92 cm. Both were able at that time to say single words, but were not combining words. Patient 5 was previously reported as a case of the CAMFAK syndrome [1281, but has been included because his clinical course and appearance are consistent with the severe form of CS. He died a t 35 months, having attained a
Fig. 2. Patient 2 at age l l V i z . The hair is thin and dry and the facial appearancenormal.The standing posture shows abnormal flexion of the hips and knees.
Cockayne Syndrome
maximal weight of 5.5 kg and head circumference of 40.5 cm. Ultraviolet light sensitivity studies were not performed on his fibroblasts.
REVIEW The neurologic, ophthalmologic, otolaryngologic, and dental manifestations in CS, abstracted from available case reports, are presented in Tables I-IV. Plots of height, weight, and head circumference based on all published anthropometric data from the American and
European literature are shown in Figure 3-7 (all reported measurements have been plotted; for some patients several serial measurements were given). Because of the nature of the reports from which the clinical data were taken, no statistical analysis has been performed. It should be noted that the data in the tables and figures are subject to biases in both directions: case reports of CS in specialty journals often failed to comment on clinical traits of patients which were not relevant to the particular specialty; and as the disease is progressive,
TABLE I. Neurologic Manifestations in Cockayne Syndrome (N Symptom or sign Developmentakognitive Weak crylpoor feeding Delayed psychomotor development
Number affected 11 50
71
Percent affected 8
38
=
131)*
References [11,47,57,65,79,94,107,108,125] [ 10,11,26,32,33,44,45,47,48,52,54,57,58, 60,64,65,79,88,94,96,98,99,101,108,
Single words/no speech
32
24
Behavior problems Intellectual deterioration Incontinent Cranial nerves External ophthalmoplegia Peripheral facial palsy Motor system Weakness Muscle atrophy “Motor abnormality” Myoclonus Movement disorder Decreased tone Increased tone
9 5 8
7
Cockayne Syndrome: Review of 140 Cases -
Martha A. Nance and Susan A. Berry Department of Pediatrics (M.A.N., S.A.B.) and Institute of H u m a n Genetics (S.A.B.), University of Minnesota, Minneapolis To define diagnostic criteria for Cockayne Syndrome (CS) and to identify in detail the complications of the condition, a comprehensive review of 140 cases of CS was performed. Criteria required for the diagnosis include poor growth and neurologic abnormality; other very common manifestations include sensorineural hearing loss, cataracts, p i g mentary retinopathy, cutaneous photosensitivity, and dental caries. The mean age of death in reported cases is 123112 years, though a few affected individuals have lived into their late teens and twenties. Prenatal growth failure, congenital structural eye anomalies, severe neurologic dysfunction from birth, and the presence of cataracts within the first 3 years of life are predictors of severe disease and early death. In contrast with other disorders of chromosome or DNA repair, cancer has never been reported in a classical CS patient, and there appears to be no predisposition to infectious complications. The wide spectrum of symptoms and severity of the disease suggest that biochemical and genetic heterogeneity exist. CS is an uncommon but devastating genetic condition which will be better understood as the biochemical interrelationships between DNA replication and repair, and between growth, homeostasis, and oncogenesis are unraveled.
INTRODUCTION Cockayne Syndrome (CS) is a rare autosomal recessive disorder of unknown pathogenesis which results in postnatal growth failure and progressive neurologic dysfunction, along with a host of other clinical symptoms and signs. Since the first report of this condition by Cockayne in 1936 [16], over 150 cases have been reported, but there has not previously been a comprehensive review of all the manifestations of the syndrome. The most extensive previous reviews are those of Cantani et al. 1121, Guzzetta [38], Houston [45],and Nyhan [87]. We present here 5 additional cases of CS, review previously reported cases, define the characteristic clinical forms of the condition, discuss atypical cases, and comment on the importance of using biochemical assays of nucleic acid metabolism to help define and diagnose the condition. The intent of this review is to serve as a resource for physicians and other caregivers of CS patients regarding the important characteristics of the syndrome, and to identify which manifestations are of particular significance in the long term prognosis of patients with the condition.
CLINICAL REPORTS Patient 1 (Fig. 1) was reported in 1976 as a case of tryptophanuria [1371. He carried that diagnosis until 1988, when, a t the age of 21, he was admitted to the University of Minnesota with acute and chronic behavior changes. At that time he had the obvious physical stigmata of CS (Fig. 1, lower right panel). He had a weight of 26.8 kg, height of 115.5 cm, head circumKEY WORDS: leukodystrophy, DNA repair, ference (OFC)of 51 cm., anhidrosis and a dry scaly rash growth failure, pigmentary over sun-exposed areas. Ophthalmologic examination retinopathy, cataracts, senshowed dry eyes, miotic pupils, a mild exotropia, mild sorineural deafness, caries, pigmentary retinopathy, optic atrophy, and hyperopia. autosomal recessive inheriHe had previously had multiple procedures for dental tance caries. Blood pressure was 106/60, and results of examination of heart and lungs were unremarkable. There was moderate hepatomegaly without splenomegaly, accompanied by chronic mild elevation of serum liver enzyme levels (SGOT 59 I.U.11, SGPT 118 I.U./l; normal range 0-50). He had intermittent diarrhea and proctalgia fugax. Secondary sexual characteristics were Received for publication February 8,1991; revision received May present. Neurologic exam showed well-developed mus16, 1991. Address reprint requests to Martha A. Nance, M.D., Depart- culature with normal strength. The intelligence quoment of Neurology-823, Hennepin County Medical Center, 701 tient (IQ) was estimated a t 30, though the patient’s social level of functioning was greater than evidenced on Park Avenue South, Minneapolis, Minnesota 55415. 0 1992 Wiley-Liss, Inc.
Cockayne Syndrome
Fig. 1. Patient 1at age 1(upper left panel), age 3 (upper right),age 9 (lower left), and age 21 (lower right). The appearance is normal a t age 1; at age 3, short stature, mild cutaneous erythema and an abnormal posture are evident; by age 9, a scaly, peeling photodermatitis is prominent, as are relatively normal-sized teeth set in a small mouth. At age 21, the face is drawn and thin, the eyes sunken, and the posture stooped due to kyphosis and flexion contractures a t the hips, knees, and ankles.
69
70
Name and Berry
formal intelligence testing. His voice had a highpitched, nasal, and mildly dysarthric quality. He had a spastic-ataxic gait; reflexes in the lower limbs were brisk and plantar responses were upgoing. An electroencephalogram (EEG) was abnormal, due to mild generalized slowing; magnetic resonance imaging (MRI) and computerized tomography (CT) scans of the brain showed a thickened cranial vault, cerebral atrophy, basal ganglia calcifications, and increased T2 signal in the superior periventricular regions bilaterally. Audiometry showed a flat 65 dB pure-tone loss from 0.5-4.0 kHz bilaterally, with slightly better speech discrimination. Qmpanograms were normal. Blood urea nitrogen (BUN) and creatinine were normal. Studies of fibroblasts showed a 37%ultraviolet (UV) survival dose of 3.0 Jouledmeter, with a normal control of 21.0 J/m; excision repair was 82%of normal. Based on the laboratory and clinical findings, the diagnosis of CS was made. He has been followed since that time for increasing gait spasticity, hearing loss, and behavior problems. Patient 2 (Fig. 2) was evaluated a t the age of lil/iz years for growth failure. She had a birthweight of 2,400 g and length of 48 cm after an uneventful pregnancy. She was gavage-fed for two months because of poor feeding. A cleft soft palate repair was performed at 10 months. Tympanostomy tubes were placed at 18 months because of recurrent otitis media and upper respiratory infections.When endocrine,gastrointestinal, and chromosome evaluation did not uncover a cause for her poor
growth (6.95 kg, 77.7 cm at lll/iz years), she was referred for evaluation. She had entirely normal eye findings; fine dry hair; mild photosensitivity; no abnormalities of heart, lungs, or abdomen; mild developmental delay; and a stooped standing posture (Fig. 2). She made noises, but no specific words, and could take only 1-2 steps. Neurologic abnormalities were more definite a t 28 months, when she had increased tone and reflexes in the lower extremities; an unsteady, wide-based gait; and mild dysmetria. Her bone age was delayed (9 months at chronological age 18 months), and an MRI scan showed questionable areas of increased T2 signal in the periventricular regions. Her fibroblasts showed at 37%UV survival dose of 4.5 J/m, with a pooled normal control dose of 17.4 Jlm; DNA repair as assayed by thymidine dimer excision was 66.2%of normal. Three additional cases have been reported from our institution [26,128], and the clinical data from these individuals were incorporated into this review. Patients 3 and 4 were sibs who were evaluated in 1988 when they were admitted for gastrostomy tube placement. In 1990, at the age of 6 years, patient 3 weighed 17.2 kg and had a height of 101 cm; his sister (age 5 years) weighed 17.5 kg and had attained 92 cm. Both were able at that time to say single words, but were not combining words. Patient 5 was previously reported as a case of the CAMFAK syndrome [1281, but has been included because his clinical course and appearance are consistent with the severe form of CS. He died a t 35 months, having attained a
Fig. 2. Patient 2 at age l l V i z . The hair is thin and dry and the facial appearancenormal.The standing posture shows abnormal flexion of the hips and knees.
Cockayne Syndrome
maximal weight of 5.5 kg and head circumference of 40.5 cm. Ultraviolet light sensitivity studies were not performed on his fibroblasts.
REVIEW The neurologic, ophthalmologic, otolaryngologic, and dental manifestations in CS, abstracted from available case reports, are presented in Tables I-IV. Plots of height, weight, and head circumference based on all published anthropometric data from the American and
European literature are shown in Figure 3-7 (all reported measurements have been plotted; for some patients several serial measurements were given). Because of the nature of the reports from which the clinical data were taken, no statistical analysis has been performed. It should be noted that the data in the tables and figures are subject to biases in both directions: case reports of CS in specialty journals often failed to comment on clinical traits of patients which were not relevant to the particular specialty; and as the disease is progressive,
TABLE I. Neurologic Manifestations in Cockayne Syndrome (N Symptom or sign Developmentakognitive Weak crylpoor feeding Delayed psychomotor development
Number affected 11 50
71
Percent affected 8
38
=
131)*
References [11,47,57,65,79,94,107,108,125] [ 10,11,26,32,33,44,45,47,48,52,54,57,58, 60,64,65,79,88,94,96,98,99,101,108,
Single words/no speech
32
24
Behavior problems Intellectual deterioration Incontinent Cranial nerves External ophthalmoplegia Peripheral facial palsy Motor system Weakness Muscle atrophy “Motor abnormality” Myoclonus Movement disorder Decreased tone Increased tone
9 5 8
7
