Clinical and Mutation Spectra of Cockayne Syndrome in India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.314579
Source of Support: None, Conflict of Interest: None
Keywords: Cockayne, ERCC6, ERCC8, India, photosensitivityKey Message: Molecular diagnosis of Cockayne syndrome is essential in prenatal diagnosis and genetic counseling for families
Cockayne syndrome is a rare autosomal recessive disorder characterized mainly by two cardinal features – microcephaly and growth retardation., Other features are developmental delay, cutaneous photosensitivity, progeroid appearance, sensorineural hearing loss, and pigmentary retinopathy. Homozygous or compound heterozygous mutations in ERCC8 and ERCC6 genes cause this disease. Seventy-five percent of the cases are due to mutations in ERCC6. We report the phenotypic and mutation spectrum of six families, with a total of eight children with Cockayne syndrome from north India.
All the patients attending the outpatient department of Medical Genetics OPD with suspected Cockayne syndrome were examined in detail. Height, weight, and head circumference of all patients were obtained and compared to the Indian Academy of Pediatrics growth charts for age and sex. Informed consent was taken from the families to store their DNA. Sequencing of coding sequences of ERCC6 (NM_000124.3) and ERCC8 (NM_000082.3) genes was performed using Sanger sequencing. The phenotypic features were compiled and mutation spectrum was analyzed. Some patients were regularly followed up in genetics OPD.
A 1 year and 10-month-old male (patient 1) [Figure 1]a, the second child of a nonconsanguineous marriage, had delay in attaining age-appropriate milestones and had progressively increasing joint contractures of both knees along with poor weight gain. His elder male sibling expired at 2 years of age and had similar illness. Examination showed deep-set eyes, rash and dryness over malar regions, stooped posture, joint contracture of knees, delayed dentition, and cachectic dwarfism with increased tone in both lower limbs. His weight was 6.67 kg (−4.5 SD), length 71.5 cm (−5 SD), and head circumference 41 cm (−5.2 SD). His brain magnetic resonance imaging (MRI) revealed generalized atrophy, hypoplasia of the corpus callosum, and delayed myelination. His hearing evaluation and ophthalmological evaluation were normal. He was detected to have a homozygous 1bp-deletion in ERCC6 (c.3112 delA) leading to a frameshift mutation, p.Arg1038Glufs*25, a novel variant. His parents were heterozygous for the same deletion [Figure 2]a and [Figure 2]b. He expired at three years of age following respiratory illness.
A 6-month-old male (patient 2) [Figure 1]b who was the third child of fourth-degree consanguineous parents was born at term with a birth weight of 2.25 kg. He developed a photosensitive rash over the malar region at 5 months of age. His elder female sibling had expired at 1 year of age with seizures, she also had a photosensitive malar rash. Examination revealed deep-set eyes, malar rash, joint contractures of both knees and ankles. His weight was 4.7 kg (−3.4 SD), length 59 cm (−7 SD), and head circumference 35.5 cm (−7 SD). His echocardiography was normal and CT scan of the head did not reveal any abnormalities.
Mutation analysis of ERCC6 showed a homozygous novel missense mutation, c.2885T>G, p.Leu962Arg which was predicted to be pathogenic by prediction software such as PolyPhen2 and Sorting Intolerant from Tolerant (SIFT) [Figure 2]c. His parents were heterozygous for the same mutation [Figure 2]d and [Figure 2]e.
Two male siblings, 11 years and 6 years old, had postnatal developmental delay, growth failure, and photosensitive rash over face. The older sibling (patient 3) [Figure 1]c had a poor scholastic performance but the younger one did well in school; both siblings had dental caries. They were born of nonconsanguineous parents. Both siblings had normal vision and hearing. The 11-year-old elder sibling (patient 4) [Figure 1]c had a weight of 13.1 kg (−4.5 SD), height of 105.8 cm (−6 SD), and head circumference of 48 cm (−3 SD). The younger sibling had a weight of 11.1 kg (−4 SD), height of 97 cm (−3.6 SD), and head circumference of 46 cm (−2.5 SD). A homozygous splice variant in ERCC6, c.543+2T>G was identified, which is a novel mutation predicted to be pathogenic by in silico analysis using Human Splicing Finder, which showed an abolition of the donor splicing site. Parents were heterozygous for the same mutation.
A 9-year-old boy (patient 5) [Figure 1]d had developmental delay, postnatal growth retardation, and photosensitivity. He was born to nonconsanguineous parents and had a delay in attaining all milestones at appropriate ages. His weight was 15 kg (less than the 3rd centile), height was 112 cm (−4 SD), and head circumference 47 cm (−3 SD). On examination, he had ataxia, spasticity of both lower limbs, and dysarthria. His facial features were mild with normal-set eyes and a less conspicuous photosensitive rash. His retinal examination showed pigmentary mottling. His head MRI showed abnormal white matter myelination for his age. Homozygous variant c.4063-1G>C was identified in the ERCC6 gene, which was already demonstrated as a pathogenic splicing mutation (partial insertion of intron 20).(6)
A 5-year-old boy (patient 6) [Figure 1]e and [Figure 1]f born to nonconsanguineous parents had prenatal growth retardation, developmental delay, and photosensitivity. There was no history of similar illness in the family. He had a malar rash, congenital cataract in eyes, hearing loss, global developmental delay, and spasticity on clinical examination. He was reviewed at 12 years of age and his facial features had become more prominent with deep-set eyes and malar rash. His spasticity, cognitive decline, and retinal pigmentary mottling worsened as he became older. His weight was 15 kg (less than 3rd centile), height 117 cm (−5 SD) and head circumference was 49cm (−3 SD). He was found to have a homozygous mutation in ERCC8 c.37G>T (p.E13*) which was a previously reported disease causing mutation.
Two siblings, born to third-degree consanguineous parents, 6-year-old boy and 3-year-old female, had postnatal growth retardation and photosensitivity. The 6-year-old boy (patient 8) had severe developmental delay and growth failure. On examination, he had photosensitive malar rash, deep set eyes, joint contractures, and spasticity of lower limbs. He expired due to respiratory illness at 6 years of age. Younger female sibling, 3 years old (patient 7) [Figure 1]g, had growth failure and developmental delay. She had a photosensitive rash, pigmentary retinal changes, and increased tone of both lower limbs. MRI brain showed cerebral atrophy. Her weight was 8 kg (−3 SD), length 88 cm (−3 SD), and head circumference 45 cm (−3 SD) They were found to have homozygous mutations in ERCC6 c.3071 -1 G>A p.G1024R, which was not reported previously and is predicted to be pathogenic by prediction software such as Automated Splice Site and Exon Definition Analyses (ASSEDA) (the nucleotide involved is the last base of exon 17 and the substitution is predicted to abolish the donor splicing site). The parents were heterozygous for the same mutation. The clinical features are summarized in [Table 1] and [Table 2].
Cockayne syndrome is an autosomal recessive condition, which was previously thought to be a DNA repair disorder and is now identified as being caused by biallelic mutations in ERCC6 or ERCC8 genes. Cockayne syndrome is very difficult to diagnose early in life. The incidence of Cockayne syndrome in Western Europe is 2.7 per million live births. The exact incidence of the condition in India is not known.
Eight children from six Indian families with Cockayne syndrome were included. There were seven males and one female. The mean age of presentation was 6 years 8 months (range, six months to 12 years). Two of them were under two years of age at the time of diagnosis. The clinical symptoms and signs were more evident as the child aged and high index of clinical suspicion is needed in infancy to diagnose this condition. Two of the eight children expired, one at three years of age and the other at 6 years of age. Four of the six families had other affected members in family. Consanguinity of parents was present in only two out of six families. Despite the relative absence of consanguinity, all patients were homozygous for the mutations, suggesting hidden consanguinity or effects of inbreeding due to remote common ancestry. The clinical features of eight children from six families are listed in [Table 1]. The most consistent clinical features were growth retardation, microcephaly, photosensitivity, and joint contractures, which are consistent with findings from previous studies., The mean birth weight was 2.3 kg (range, 2–3 kg). Even though sensorineural hearing loss is considered a feature of this disorder, only one patient in our cohort was identified to have this. Retinal dystrophy was identified in two of the eight children. Abnormal brain imaging is a well-recognized feature of Cockayne syndrome. In our cohort, neuroimaging could be done only in four patients, and three of them had abnormal findings on MRI brain in the form of cerebral atrophy and myelination changes.
For all the eight patients diagnosed clinically, diagnosis was confirmed by molecular testing. This stresses the importance of the features such as growth retardation, developmental delay, photosensitivity and deep-set eyes as good clinical clues in the diagnosis of Cockayne syndrome. Biallelic mutations were seen in ERCC6 in seven out of eight children (87.5%). Only one out of eight children had a biallelic ERCC8 mutation (12.5%). ERCC6 mutations were most common, as described in the literature. The ERCC6 mutations included one missense mutation (patient 2), three intronic mutations that likely affected splicing (patients 3, 4, 5, 7, and 8) and one frameshift mutation that caused premature termination and truncation of protein (patient 1). More than 90 different ERCC6 mutations have been described so far, of which the majority are either nonsense or frameshift mutations. Thirty-nine mutations have been described in ERCC8 which include nonsense mutations, missense mutations, and large partial gene deletions. No single type of mutation seems to predominate.,,
Cockayne syndrome should be suspected in any child with photosensitivity, microcephaly, and growth retardation. Using clinical criteria alone diagnosis can be made with certainty in 90% of the children. High index of suspicion should be there to recognize patients in early infancy and childhood. However, establishing an unequivocal diagnosis by molecular methods in the proband as early as possible is essential in providing counseling for the families and for prenatal diagnosis.
We acknowledge the support and co operation of the families. We also acknowledge the support of Indian Council of Medical research, Grant number 63/8/2010-BMS Indian Council of Medical Research, Bio Medical Science.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2]