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Cockayne syndrome is a multi‐systemic, autosomal recessive disease characterised by postnatal growth failure and progressive multi‐organ dysfunction. The main clinical features are severe dwarfism (<−2 SD), microcephaly (<−3 SD), psychomotor delay, sensorial loss (cataracts, pigmentary retinopathy, and deafness), and cutaneous photosensitivity. Here, 13 new cases of Cockayne syndrome are reported, which have been clinically diagnosed and confirmed using a biochemical transcription assay. The wide clinical variability, ranging from prenatal features to normal psychomotor development, is emphasised. When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered when presented with growth retardation, microcephaly, and one of the suggesting features such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging.
Cockayne syndrome is a multi‐systemic, autosomal recessive disease (MIM 216400) characterised by postnatal growth failure and progressive multi‐organ dysfunction, first described in 1936.1 The main clinical features are severe dwarfism (<−2 SD), microcephaly (<−3 SD), psychomotor delay, sensorial loss (cataracts, pigmentary retinopathy, and deafness) and cutaneous photosensitivity. Two types have been defined:2 type I, corresponding to a less severe form (symptoms occurring after birth); and type II, corresponding to a more severe infantile form with prenatal growth failure, severe neurological dysfunction, and premature death. Almost all Cockayne syndrome cases are due to mutations of the CSA gene on chromosome 5 or mutations of the CSB gene on chromosome 10q.3,4
Here, we report on 13 new cases of Cockayne syndrome whose diagnoses have been confirmed by transcriptional assays, and emphasise the wide clinical variability ranging from prenatal features to normal psychomotor development. The observation of multi‐systemic involvement in some severe forms suggests that mitochondrial dysfunction should be considered as a differential diagnosis.
Thirteen patients followed by eight clinicians from different French genetics medical centres were included in the study. The only criterion for inclusion was a positive biochemical diagnosis by the French reference laboratory (Pr Sarasin)—that is, 24 hours after UV irradiation normal fibroblasts have recovered a normal level of RNA synthesis (RRS); the range of RRS deficiency in our patients was 60–90% of controls, associated with a normal level of unscheduled DNA synthesis (UDS) following UV irradiation (data not shown).
Fibroblasts were established from unexposed skin biopsy specimens as previously described,5 and routinely grown in MEM, 15%, FCS, 1% glutamine, and 1% antibiotics.
UDS was measured, as previously described,5 on patients' fibroblasts after UV‐C irradiation (mainly at 254 nm). The doses routinely used ranged from 0 to 20 J/m2.
RRS was carried out on patients' fibroblasts as described by Lehmann,6 except that the measure of RNA synthesis was quantified by autoradiography in the same way as for UDS. Cells were UV‐C irradiated at 20 J/m2 and RNA synthesis was measured for one hour, 23 hours after UV irradiation.
The series included nine males and four females. There were three familial cases with two patients (1–2, 7–8, and 10–11) in offspring of each family (1, 6, and 8). Average age of diagnosis was below 5 years old, ranging from 1 year (two recurrent cases in offspring) to 10 years. Five died between 4 and 7 years of age (patients 2, 4, 7, 8, and 9); eight are still alive.
Intrauterine growth retardation (IUGR) and microcephaly were noted in six cases. In addition, vermis atrophy (patient 11) and cardiomyopathy (patient 4) were occasionally detected prenatally.
Among postnatal manifestations, enophthalmia and growth failure were noted in all cases. Photosensitivity, defined as abnormal reaction to sun exposure (as papulovesicular eruption, rash with oedema, or atrophic scars) was observed in half of the patients (6/13). Among ophthalmological findings, cataracts, optic atrophy, and pigmentary retinopathy were found respectively in 8/13, 5/9, and 6/9. Sensorineural deafness was detected in 7/13 cases.
Death was due to cachexia in at least three patients, although gastrostomy was performed. Patient 2 died of bleeding oesophageal varices due to portal hypertension not related to viral or mitochondrial dysfunction.
The presenting symptoms were sometimes atypical, including cardiomyopathy (patient 4), telangiectasia and intraocular calcifications responsible for blindness in two siblings (patients 1 and 2), and flat vertebral bodies in another case (fig 11;; patient 6).
Finally, unusual features were observed in a few cases: cardiomyopathy, vascular liver, telangiectasia, and flat vertebral bodies (fig 11).
Among the laboratory findings, anaemia was detected in two patients (2 and 9), partly due to cachexia for patient 9. Mild serum aminotransferase elevation (2N) was noted in 5/13 patients without any other hepatic dysfunction. Lactic acidaemia, high lactate levels in cerebrospinal fluid, or abnormal excretion of organic acids detected by urinary chromatography (in patients 1, 2, 3, 5, and 12) prompted us to test the mitochondrial respiratory chain. Enzyme assays performed on muscle and/or skin fibroblasts were normal.
We report here the clinical manifestations of 13 new cases of Cockayne syndrome confirmed by biochemical assays, and compared this series to previous reports—that is, 140 cases of Cockayne syndrome reviewed but not all confirmed by transcription test assessment,2 and 29 patients showing the characteristic defect of CS cells.7
As previously described, growth failure (height and weight <−2 SD), microcephaly (<−3 SD), and variable degree of psychomotor retardation appear to be consistently observed. Child 1 is the only patient in the series with no neurodevelopmental delay, but is only 6 years old.
The only consistent dysmorphic feature is profound enophthalmia or sunken eyes, due to the lack of subcutaneous orbital fat.2,8,9 However, this feature is not present in the early stages as shown by fig 11;; it becomes more obvious with time. In contrast, features usually considered as mandatory for Cockayne syndrome diagnosis were not consistently observed in our series; these included thin skin and/or photosensitivity, cataracts and pigmentary retinopathy, sensorineural deafness, and intracranial calcifications with ventricular dilatation on cerebral imaging.
Finally, the presenting symptoms were quite unusual in our series, leading to consideration of other diagnoses. In patients 1 and 2, bilateral telangiectasia and intraocular calcifications were present in the neonatal period, leading to blindness; the initial diagnosis was COATS disease (MIM 300216). Conjunctival telangiectasia is usually described in xeroderma pigmentosum which may share others common features with Cockayne syndrome.10 Intrauterine growth retardation and microcephaly suggested a mitochondrial defect as the primary diagnosis in six patients, especially when associated with ataxia, dilated cardiomyopathy, pigmentary retinopathy, and/or cerebral calcifications. Patient 6 was first referred for skeletal dysplasia with flat vertebral bodies. Interestingly, a similar case has been described,9 suggesting that spine anomalies are possible manifestations of Cockayne syndrome.
Based on our series, we emphasise the wide clinical presentations in Cockayne syndrome. In addition, some degree of phenotypic variability has also been observed within the same family.11 We conclude that the diagnosis of Cockayne syndrome is not always easy in the first months of life when cardinal features are not present; it should be considered when dealing with growth retardation and microcephaly.
Fundings: this work was supported by the GIS–Institut des Maladies Rares
Competing interests: none declared
Consent was obtained for publication of the figure