Clinical Description
Cockayne syndrome is characterized by growth failure, microcephaly, neurodevelopmental delays, cutaneous photosensitivity, sensorial impairment, and dental anomalies [Laugel 2013].
Before the molecular genetics of Cockayne syndrome was understood, it was thought to have a single, discrete phenotype: classic Cockayne syndrome. Importantly, it is now recognized that Cockayne syndrome spans a continuous phenotypic spectrum without clear thresholds and includes the following but somewhat arbitrary subtypes [Nance & Berry 1992]. A quantitative severity scoring system has been designed to account for this continuous spectrum and to help clinicians follow the course of the disease in affected individuals [Spitz et al 2021].
CS type I, the "classic" form
CS type II, a more severe form with symptoms present at birth (overlapping with cerebrooculofacioskeletal syndrome [COFS])
CS type III, a milder form
Cerebrooculofacioskeletal (COFS) syndrome, the most severe end of the phenotypic spectrum of CS, with findings identifiable during fetal life
To date, hundreds of individuals have been identified with Cockayne syndrome and biallelic pathogenic variants in ERCC6 or ERCC8. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Cockayne Syndrome: Comparison of Phenotypes by Select Features
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Feature | CS Type I | CS Type II | CS Type III | COFS Syndrome |
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Typical age of onset
| Early childhood (age <2 years) | At birth (severe) | Late childhood (age >2 years) | During fetal life |
Growth failure
| Prenatal growth normal; onset of growth failure age <2 years | Onset at birth | Late childhood (age >2 years) | Onset during fetal life |
Photosensitivity
| Clinically variable | Clinically variable | Clinically variable | Clinically variable |
Vision issues
| Cataracts, pigmentary retinopathy, optic atrophy | Congenital cataracts , pigmentary retinopathy, optic atrophy | Cataracts, pigmentary retinopathy, optic atrophy | Congenital cataracts, pigmentary retinopathy, optic atrophy |
Hearing issues
| Progressive neurosensorial hearing loss | Progressive neurosensorial hearing loss | Progressive neurosensorial hearing loss | Progressive neurosensorial hearing loss |
Neurologic abnormalities
| Developmental delay, intellectual disability, cerebellar ataxia, spasticity, peripheral neuropathy | Severe developmental delay, severe intellectual disability, cerebellar ataxia, spasticity, peripheral neuropathy | Intellectual disability, dementia, cerebellar ataxia, spasticity, peripheral neuropathy | Arthrogryposis, severe developmental delay, cerebellar ataxia, spasticity, peripheral neuropathy |
Skin cancer predisposition
| None | None | None | None |
Progression
| Progresses throughout childhood | Almost no psychomotor development | Progresses throughout childhood & adulthood | Almost no psychomotor development |
Prognosis
| Death during 1st or 2nd decade (mean age 16 years) | Death usually in 1st decade but prolonged survival possible in a few cases | Long-term survival into adulthood | Death usually in 1st decade but prolonged survival possible in a few cases |
Typical facial appearance ("cachectic dwarfism" w/sunken eyes)
| Present in early life | Present in early life | May appear progressively in late stages | Distinct morphologic features w/prominent nasal root & prominent metopic suture; no clear cachectic appearance in most cases |
COFS = cerebrooculofacioskeletal syndrome; CS = Cockayne syndrome
CS Type I
Presentation. Prenatal growth is typically normal. Birth length, weight, and head circumference are normal. Within the first two years, however, growth and development fall below normal. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth centile.
Progression. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability. Brain MRI reveals white matter dysmyelination and progressive cerebral and cerebellar atrophy. Photosensitivity is variable, but individuals are not predisposed to skin cancers.
Additional clinical abnormalities occurring in 10% or more of individuals include the following:
Neurologic. Increased tone/spasticity, hyper- or hyporeflexia, stooped standing posture, abnormal gait or inability to walk, ataxia, incontinence, tremor, abnormal or absent speech, seizures, weak cry / poor feeding (as an infant), muscle atrophy, and behavior abnormalities
Ophthalmologic. Enophthalmos, pigmentary retinopathy (60%-100%), abnormal electroretinogram, cataracts of various types (15%-36%), optic atrophy, miotic pupils, decreased or absent tears, strabismus, nystagmus, photophobia, narrowed retinal arterioles
Hearing. Sensorineural hearing loss
Dental. Absent or hypoplastic teeth, enamel hypoplasia, delayed eruption of deciduous teeth, and malocclusion. Enamel anomalies frequently lead to severe dental caries [
Bloch-Zupan et al 2013].
Skeletal. Radiographic findings of thickened calvarium (due to microcephaly), sclerotic epiphyses, vertebral and pelvic abnormalities
Endocrine. Undescended testes, delayed/absent sexual maturation, diabetes
Gastrointestinal. Elevated liver function tests, enlargement of liver or spleen, gastroesophageal reflux
Death typically occurs in the first or second decade. The mean age of death is 16 years, although survival into the third decade has been reported [Natale 2011].
CS Type II
Children with severe CS have evidence of growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye are present in 30% of individuals. Affected individuals may have some contractures of the spine (kyphosis, scoliosis) and joints in neonatal or early postnatal life. Affected children typically die by age five years [Natale 2011]. CS type II partly overlaps with cerebrooculofacioskeletal (COFS) syndrome.
CS Type III
DNA sequencing has confirmed the diagnosis of CS type III in some individuals who have clinical features associated with CS but whose growth and/or cognition exceeds the expectations for CS type I [Natale 2011, Baez et al 2013]. Major features only become apparent after age two years.
COFS Syndrome
COFS syndrome is the most severe subtype of the CS spectrum and can be identified during fetal life. Similar to individuals with CS type II, individuals with COFS syndrome present with severe prenatal growth failure, severe developmental delay / intellectual disability from birth, axial hypotonia, peripheral hypertonia, and neonatal feeding difficulties. COFS syndrome is additionally defined by the presence of arthrogryposis and usually the combination of extreme congenital microcephaly and congenital cataracts [Laugel et al 2008].
COFS syndrome can be recognized during prenatal surveillance and is responsible for cases of spontaneous fetal deaths.
Neuropathology
In all forms of Cockayne syndrome, a characteristic "tigroid" pattern of demyelination in the subcortical white matter of the brain and multifocal calcium deposition, with relative preservation of neurons and without senile plaques, amyloid, ubiquitin, or tau deposition, has been observed together with arteriosclerosis [Weidenheim et al 2009, Hayashi et al 2012].
Genotype-Phenotype Correlations
To date no clear genotype-phenotype correlations for ERCC6 or ERCC8 have been identified. In one study, individuals with pathogenic variants in ERCC8 appeared to have significantly less severe manifestations than ERCC6 at the time of the diagnosis [Spitz et al 2021].
For individuals with pathogenic variants in ERCC6, variants upstream of a transposon called PiggyBac transposable element-derived protein 3 in intron 5 of ERCC6 were found to be associated with less severe features than pathogenic variants downstream of that transposon insertion [Damaj-Fourcade et al 2022].
Nomenclature
The term "cerebrooculofacioskeletal (COFS) syndrome" and its former synonym, Pena-Shokeir syndrome type II, have been used to refer to a heterogeneous group of disorders characterized by congenital neurogenic arthrogryposis (multiple joint contractures), microcephaly, microphthalmia, and cataracts. The original cases of COFS syndrome, described by Pena & Shokeir [1974] among First Nations families from Manitoba, have since been shown to be homozygous for a pathogenic variant in ERCC6. COFS syndrome is now regarded as a prenatal form of CS, partly overlapping with CS type II and including the most severe cases of the CS phenotypic spectrum [Laugel et al 2008].