The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Abstract

Purpose: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established.

Methods: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians.

Results and conclusion: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.Genet Med 18 5, 483-493.

Figure 1

Clinical features in Cockayne syndrome (CS). (a) Clinical features in our cohort in order of decreasing frequency. The asterisk indicates that the denominator is dependent on an investigation being performed; for example, 71 patients had serum analysis of liver function. Our data are compared with those presented by Nance and Berry (the values shown are independent, not cumulative). The considerable differences reflect the fact that our data have been systematically collected from primary sources, whereas the review was largely based on published case reports. (b) Cumulative frequency of features, corrected for survival. (c) Detailed information on clinical features, ordered as in (a). Grey bars are descriptive, white bars illustrate clinical progression, and black bars indicate management. n, number of patients in each analysis. (d) Chart illustrating how participants reached their current diagnosis. For “biopsy only,” “biopsy and genetic,” and “genetic only,” this indicates that a confident clinical diagnosis was not given beforehand.

Figure 2

Changing features in Cockayne syndrome (CS). (a–l) Study participants (ages shown). Some individuals look completely normal early in life, whereas others may have subtle clues to the diagnosis, including crowded facial features and small eyes. While loss of subcutaneous fat, with development of the classic CS appearance (a, b, j), is not a feature in all, a sunken appearance to the eyes often develops with a loss of orbital fat. Patients g and h are sister and brother. The girls appearing in j are identical twins. Older individuals with CS are shown in k. Note also the flexed upper limb posture sometimes seen in patients with CS (l).

Figure 3

Growth and development in Cockayne syndrome (CS). (a) Growth parameters are in the low normal range at birth, but rapid reduction in growth velocity to growth arrest occurs postnatally (PN). Z-scores were calculated using the LMS method on 1990 British Growth Reference data. n, number of patients plotted. Mean values ± 1 SD are shown. (b) Developmental ranges in CS. Ages at which participants achieve developmental milestones are shown. n, number of patients for whom age at attainment was available.

Figure 4

Prognostic factors in Cockayne syndrome (CS). The occurrence of cataracts before 3 years of age is the single most valuable prognostic factor in CS (a), having statistically extremely significant associations with reduced survival and shorter intervals to development of several other clinical features associated with reduced quality of life. Severe photosensitivity is associated with earlier onset of contractures, but not other factors affecting quality of life, or mortality (b). Having mutations in CSB (rather than CSA) has a borderline significant association with reduced survival only (c). For all plots, Kaplan–Meier estimates of the survival curve and 95% confidence intervals are shown. Statistical tests are Mantel–Haenszel tests of difference in the survival curve between groups.