Cockayne syndrome in adults: review with clinical and pathologic study of a new case

Abstract

Cockayne syndrome and xeroderma pigmentosum-Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31(1/2) years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum-Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known.

Figure 1

Patient at ages 9 (A), 13 (B), 17 (C), and 28 years (D). Note the cheerful expression and that the characteristic Cockayne facies (sunken eyes, sharp nose, jutting chin, emaciation) was not striking, even at age 17 years.

Figure 2

Computed tomographic scans at age 25 years showing (A) thickening of the calvarium, severe panventricular enlargement, and calcification of the basal ganglia and (B) extreme thinning of the white matter, widened sulci, and thin bilateral subdural collections.

Figure 3

A, Artery of the circle of Willis with 60% occlusive atherosclerosis of the lumen (L) (hematoxylin-eosin stain; original magnification, ×88). B, Coronal section of the cerebrum that parallels the earlier findings on computed tomography. C, Whole-mount section of the atrophic cerebellar vermis (hematoxylin-eosin stain).

Figure 4

A, Low-power view of white matter stained with Luxol fast blue–periodic acid–Schiff shows hypercellularity and is pale blue, indicative of demyelination (original magnification, ×347). B, High-power view of white matter stained with Luxol fast blue–periodic acid–Schiff shows pleomorphic oligodendrocytes (arrows) (original magnification, ×1375). C, Calcification (arrows) in the basal ganglia (hematoxylin-eosin stain; original magnification, ×602). D, Collagen IV immunostain demonstrates string vessels (arrow) (original magnification, ×400). E, Skeletal muscle showing small group atrophy (arrows) consistent with neurogenic atrophy (hematoxylin-eosin stain; original magnification, ×641). F, Toluidine blue–stained 1 micron–thick section of skeletal muscle showing marked nuclear atypia (arrows) (original magnification, ×1280).

Figure 5

A, Low-power view of the anterior chamber of the eye demonstrating iris atrophy, a mioticpupil, and an abnormally flattened anterior surface of the cataractous lens (hematoxylin-eosinstain; original magnification, × 4); inset: higher-power view of the pupil showing a pigmented, fibrous pupillary membrane (arrow) and posterior synechiae to the lens (original magnification, ×40). B, Sclerosis of the ciliary body and ciliary processes (asterisks) (hematoxylin-eosin stain; original magnification, ×16); inset: pigmentary dispersion of the iris with melanophages studding the anterior iridic border (arrows) and absence of the iris dilator muscle (arrowhead) (hematoxylin-eosin stain, original magnification, ×63). C, Marked atrophy of the retina with wrinkling of the inner limiting membrane (asterisk), intraretinal pigment migration (arrow) and atrophy, and hyperplasia of the underlying retinal pigment epithelium (arrowheads) (hematoxylin-eosin stain; original magnification, × 160). D, Atrophy and gliosis of the optic nerve (hematoxylin-eosin stain; original magnification, × 12.5).

Figure 6

Midmodiolar section of the cochlea. All cochlear turns show diffuse and severe degeneration of sensory, neural, and supporting structures, including loss of the organ of Corti, severe degeneration of the stria vascularis and spiral ligament, near-total loss of cochlear neurons (spiral ganglion cells), and collapse of the endolymphatic space (scala media). There is also severe atrophy of the saccular macula (hematoxylin-eosin stain; original magnification, ×19).