ABSTRACT

XP/Cockayne (XP/CS) Overlap SyndromeCS is a rare (approximately 1/100,000 live births) autosomal recessive disorder characterized in part by progressive neurodegeneration, a progerioid (premature aged, wizened) appearance and photosensitivity without development o f skin cancer.23,24 The neurodegeneration is associated with demyelination, rather than with neural cell degeneration, as is seen in cases o f XP associated with neurological disease.25 Three forms o f CS have been delineated: CS Type I, also known as “classic CS”, CS Type II, “Cerebro-Oculo-Facial-Skeletal syndrome (CO FS)”, the “Pena-Shokeir syndrome, Type II” or “connatal C S”, and CS Type III. Some authors distinguish between CS Type II and COFS; we shall consider them synonymous here. CS Type II is the most severe, with abnormalities mani­fested in utero and gross deformities present at birth. In CS Type I, abnormalities are not apparent at birth but appear in early childhood. In CS Type III the disease is milder with later onset, in some cases as late as the third decade o f life. The X P /C S overlap syndrome may constitute a fourth form, but individual cases may fall within one o f the three other forms, particularly the COFS syndrome. W hen it occurs without sun-sensitivity, CS has variable phenotype.26CS Type I is characterized by normal prenatal growth but with growth and developmental abnormalities arising in the first two years after birth. Following onset, growth retardation becomes severe, so that at the end o f the course o f the disease, height, weight and head circumference are well below the fifth percentile. A very characteristic finding is recession o f the eyes into their sockets, due to lack o f post-orbital fat. This, along with lack o f fat in facial tissues, contributes to a “wizened” faces forming part o f a progeroid phenotype. Dental caries, due to decreased salivation and defective innervation o f the salivary glands, is a frequent feature. Patients may have a characteristic “horse rider” gait. Neurodegeneration is progressive and death usually occurs by seven years o f age.COFS (CS Type II) is even more severe than CS Type I, w ith gross abnormalities becoming apparent in utero. These abnormalities are clearly manifest at birth and progress rapidly afterwards. CS Type III is typically much less severe with signs and symptoms occurring much later in life.CS o f any type tends to be associated with spasticity, increased deep tendon reflexes and joint disease. X-ray examination reveals calcifications o f basal ganglia o f the brain. Neuropathologic changes are associated w ith demyelination, rather than the neuronal degeneration characteristic o f the neurodegenerative disease seen in some cases o f XP. Approximately 75 percent o f cases o f CS have been found to be due to a biallelic m utation in the E RC C 6/C SB gene. M ost o f the remaining 25 percent o f cases are due to a m utation in the E R C C 8/C SA gene. M utations in E R C C 8/C SA or ERC C 6/C SB cause defective T C R o f U V damage.27 There may also be subde transcription defects.29'30Very few cases o f CS are due to a m utation in xhcXPB, X PD or X P G genes; some o f these also have features o f XP and are thus examples o f the X P /C S overlap syndrome. A tiny subset o f cases is due to a gene(s) that has no t yet been identified.Patients w ith CS, no t in complem entation groups A or B, were formerly identified as in complementation group C , C S-C .31 This group has subsequently been abandoned.20 Some o f these patients had biallelic m utations in X PD .Patients w ith the X P /C S overlap syndrome(s) have very variable phenotypes and it is perhaps unwise to attem pt to generalize regarding them. However, their XP features at least include early freckling, accompanied by dryness o f the skin in sun-exposed areas and in some cases by skin cancers. Their CS features tend to include mental retardation, spasticity, short stature and hypogonadism, but not skeletal dysplasia, although there are exceptions. XP-B/CS Overlap SyndromeTo date, seven mutations in ERC C 3/X PB have been identified in six families.32 Each family has one or more individuals w ith either XP (one family), T T D (one family), or the X P /C S overlap syndrome (four families). The very limited range o f these mutations may be related to the fact that the XPB protein is a helicase, active in bo th N ER and transcription and essential for both o f them. In contrast, the X P D protein, although a helicase active in both N E R and transcription,

is essential only for the former.32,33 Thus a m utation in X P B is m uch more likely to be lethal than one in X PD .The six families w ith XPB mutations have been extensively studied by Oh, et a l32 The first XPB patient identified,34,35 (their Family III32) was found to have a severe form o f the X P /C S overlap syndrome.36 XP signs/symptoms included extreme sensitivity to sunlight, w ith blistering noted in infancy, dyspigmentation and multiple skin cancers w ith onset at age 15 years. CS signs/symptoms included severe dwarfism, microcephaly, microphthalmia, sensorineural deafness, severe mental retardation ( IQ o f 40 but w ith good social skills), corneal scarring, cataracts, pigmentary retinal degeneration, optic atrophy, abnormal (flat) retinogram, hypereflexia, ataxia, decreased nerve conduction velocity, enlarged cerebral ventricles (brain), basal ganglia calcifications and immature sexual development. The patient died at 33 years o f age o f cardiovascular disease.A second family (Family II32) had two brothers with mild X P /C S overlap syndrome. They were originally reported by Scott, et al,37 with the XPB classification subsequendy carried out by Vermeulen et al;38 The XP features in these patients consisted o f severe sunburn at approximately six weeks o f age and early freckling-like dyspigmentation. Neither had developed skin cancer when studied at ages 38 and 41, respectively. However, CS features were somewhat more severe, consisting o f short stature, sensorineural hearing loss which began at the age o f four years and late onset hyperreflexia, other clinical neurological deficiencies, decreased nerve conduction velocity, enlarged central ventricles, demyelinating neuropathy, retinopathology and immature sexual development.A th ird family (Family IV32) consisted o f a 27 year-old man w ith a severe form o f X P /C S overlap syndrome from Slovenia.39 X P features included sun hypersensitivity, dyspigmentation and atrophy o f sun-exposed skin, telangiectasias and recurrent eyelid squamous cell carcinoma. CS features included growth and mental retardation, sensorineural deafness, optic atrophy, pigmen­tary retinopathy, ataxia, decreased nerve conduction velocity, enlargement o f central ventricles, cerebellar atrophy and calcifications o f the basal ganglia. H e died o f end-stage renal failure at 31 years o f age.A fourth family (Family V32), consisted o f a 10 year-old girl w ith severe X P /C S overlap syn­drome from Germany. XP signs/symptoms consisted o f severe sunburn at age two weeks and freckling on sun-exposed skin since early childhood. She had no t developed any skin cancers when evaluated at 10 years o f age. CS signs/symptoms consisted o f increasing growth retardation, bird-like faces, progressive hearing loss beginning at age 7 years and a progressive loss o f mental development. A lthough she could walk at age 20 months, she subsequendy developed ataxia, abnormal balance, central coordination disability and interm ittent tremor. She had hyperopia but no t optic nerve atrophy or cataracts. Patellar and Achilles tendon reflexes were absent; the Babinski sign was negative.A fifth (Family I) and sixth (Family VI) families reported by O h, et al32 had only XP and T T D respectively.All o f these XPB families* cells were hypersensitive to U V irradiation and showed very low unscheduled D N A synthesis (UDS) levels (reduced to 4-10% o f normal levels) following U V ir­radiation. Recovery o f RNA synthesis (RRS) was also low following U V irradiation. Oh, et al also showed that more severely affected patients with XP-B mutations had less residual XP-B activity than less severely affected ones.32 XP-D/CS Overlap SyndromeThere are three reports o f the X P /C S overlap syndrome falling w ithin the D complementation group o f XP.4042Cells derived from Individuals who have clinical features o f CS and also skin changes, includ­ing skin cancers, typical o f XP, have been found to have biochemical features typical o f XP and to fall w ithin the D complementation group o f XP.43 Cellular functional assays o f cells from some patients with the COFS phenotype show sensitivity to UV, decreased UD S following U V radia­tion and complementation o f these features by the X P-D product.44