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|LETTERS TO EDITOR
|Year : 2018 | Volume
| Issue : 5 | Page : 1488-1490
Cockayne syndrome in siblings
PR Sowmini, M Sathish Kumar, S Sakthi Velayutham, G Revathy, S Arunan
Department of Neurology, Stanley Medical College, Chennai, Tamil Nadu, India
|Date of Web Publication||17-Sep-2018|
Dr. P R Sowmini
Department of Neurology, Stanley Medical College, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sowmini P R, Kumar M S, Velayutham S S, Revathy G, Arunan S. Cockayne syndrome in siblings. Neurol India 2018;66:1488-90
In 1936, Edward Cockayne first described Cockayne syndrome (CS) as dwarfism with retinal atrophy and deafness. After 10 years of follow-up of these patients, he added new clinical features such as progressive joint contractures and hearing loss. In 1950, Neil and Dingwall reported the presence of brain calcification in siblings with CS. In 1992, Nance and Berry reviewed 140 patients with CS and proposed major and minor diagnostic criteria and classified CS as mild, moderate (classic), and severe. CS is characterized by postnatal growth failure and progressive neurologic dysfunction with cachectic appearance. Other features include retinal dystrophy, photosensitivity, cataract, and microcephaly. CSA and CSB genes are mutated in 30% and 70% of CS cases, respectively.
Two siblings (elder sister and younger brother), born out of nonconsanguineous parentage were brought by their parents for progressive difficulty in walking. The first child was a 22-year old female patient who had normal growth and development till the age of 12 years. Thereafter, her parents noticed unsteadiness in walking and tightness of her lower limbs. Her facial appearance also started changing with signs of premature aging. She progressively worsened and suffered occasional falls. She had attained her menarche at the age of 12 years and her menstrual cycles were regular. On examination, she was cachectic and stunted with a height of 136 cm and a weight of 34 kg. Her head circumference was 46 cm, which qualified for microcephaly [Figure 1]. She had malaligned teeth. She had normal secondary sexual characteristics. The cardiac evaluation was normal. She had corneal opacity in her left eye. Neurological examination revealed appendicular and axial ataxia, spastic paraparesis, bilateral sensory neural hearing loss, and mild cognitive decline. Nerve conduction study revealed sensorimotor axonal polyneuropathy of both upper and lower limb nerves. Her electroencephalogram (EEG) was normal. Magnetic resonance imaging (MRI) revealed bilateral basal ganglia calcification, a thin corpus callosum, and cerebral atrophy [Figure 2] and [Figure 3].
|Figure 2: MRI brain T1 sagittal section of first sibling showing atrophy of brainstem and cerebellum|
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|Figure 3: MRI brain T2 axial section showing diffuse cortical atrophy and prominent dilated ventricles|
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The second sibling, a 20-year old male patient, was brought with similar complaints that had been occurring since 12 years of age. He had a similar facial appearance as his sister. He was cachectic with a height of 140 cm and a weight of 36 kg. He had microcephaly (his head circumference was 48 cm) and mild sensory neural hearing loss. He had appendicular ataxia and scissoring of gait due to spastic paraplegia. He had left eye optic atrophy, and cardiac evaluation showed premature accelerated aging in the form of aortic valve (AV) sclerosis [Figure 4] and dilatation of ascending aorta. He also had mild cognitive decline and normal secondary sexual characters. The nerve conduction study revealed sensorimotor axonal polyneuropathy of all four limbs. The electroencephalogram (EEG) showed a normal awake record. Magnetic resonance imaging (MRI) showed bilateral basal ganglia calcification, a thin corpus callosum, and cerebral atrophy, features that were similar to that of his sister.
|Figure 4: MRI brain FLAIR coronal section showing diffuse cerebellar atrophy|
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CS is a very rare syndrome with an incidence of 1 in 2.5 lakhs. At birth, children with CS appear normal. As they grow, they tend to show growth failure, sunken eyes with loss of subcutaneous fat giving a characteristic progeroid facies, and psychomotor retardation. Dental caries and enamel hypoplasia are frequently reported in CS. Neurological manifestations account for most of the morbidity of the disease. Patients develop microcephaly, ataxia, spastic paraparesis, and peripheral neuropathy (which may also contribute to ataxia). A predominantly axonal pattern of neuropathy is found in nerve conduction studies. Both the siblings reported in this study exhibited typical neurological features of CS. Patients with CS can have mixed and pure sensorineural hearing loss. The important ophthalmological features are corneal opacity, cataract, optic atrophy, and salt and pepper pigmentary retinopathy. In our cases, the sister had corneal opacity and the brother had optic atrophy. The development of cataract before 3 years of age is considered a poor prognostic factor. When it comes to musculoskeletal deformities, dwarfism is the most common feature and was present in both of our siblings. Other features include contractures, kyphoscoliosis, and a stooped posture. CS patients are more susceptible to stroke as they can develop accelerated hypertension due to premature aging. Arteriovenous sclerosis and ascending aorta dilation are the main cardiovascular features seen in CS. Ascending aorta dilation is extremely rare but was present in one of our siblings. Secondary sexual characters are usually normal. They can develop renal failure due to arteriosclerosis. They may exhibit exaggerated response to opioids and benzodiazepines, hence, cautious use of these drugs is advised. Metronidazole is best avoided in CS, as cases of fulminant hepatic failure have been reported in the literature following the usage of the drug. Thickened calvarium is seen in X-ray of the skull. The characteristic MRI findings are atrophy of the cerebellum, cerebrum and brainstem, a thin corpus callosum, and calcifications in bilateral basal ganglia. White matter signal intensity abnormalities can be seen due to hypomyelination.
CSA and CSB genes are localized to 5q 12-q31 and 10q 12-q31, respectively. It is interesting to note that though CS patients have photosensitivity, they have lesser incidence of ultraviolet (UV)-related skin cancer than do patients with xeroderma pigmentosa (XP). This is due to the fact that the XP (xeroderma pigmentosum) cell has a high mutation frequency in response to ultra-violet rays compared with CS. The protein products of CSA and CSB genes are necessary for an intact transcription-coupled nucleotide excision repair pathway, which repairs interstrand cross links (ICLs). ICLs are cytotoxic, and hence, deoxyribose nucleic acid (DNA) replication is affected.
CS should be suspected in any child with microcephaly and postnatal growth failure, and any two of the following features: cold hands and feet, bilateral hearing loss, photosensitivity, joint contractures, intention tremor, typical facial features, loss of body fat, and cataract. Genetic testing for CSA and CSB confirms the diagnosis. Clinicians should prognosticate the illness and provide parental counseling. Annual eye, ear, blood sugar, blood pressure, and liver function tests are warranted. Periodical review with a physiotherapist is advised. Calcium channel blockers and angiotensin converting enzyme inhibitors are the first-line drugs given for treating hypertension. Proton pump inhibitors can be used for gastro-esophageal reflux disease (GERD). Levodopa may be tried in the presence of intentional tremor.
CS is very rare with most reports being found in journals of pediatrics, dermatology, and orthopedics. The axonal type of peripheral neuropathy found in our patients has not been reported so far in CS. Dilatation of the ascending aorta, which is a sign of premature atherosclerosis, has been very rarely reported. Photosensitivity, a common association in CS, was not present in our patients.
CS can be suspected based on typical facial features along with postnatal growth failure and microcephaly. The diagnosis can be confirmed by genetic testing which may not be possible in developing/underdeveloped nations. The principal clinical implication of identification of this syndrome is to watch out for early atherosclerosis and its complications (stroke, myocardial infarction, accelerated hypertension, and renal failure), which can facilitate appropriate and timely treatment. The pathology of CS resembles normal aging, and hence, further research related to the disease may throw some light on the mechanisms of aging.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]