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Home , Bloom syndrome, Dyskeratosis congenita, ERCC1, ERCC2, Postreplication repair, Trichothiodystrophy

178 Arch Dis Child 1998;78:178–184

REGULAR REVIEW Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from

DNA repair disorders

C GeoVrey Woods

Over the past 30 years a number of rare DNA Exogenous DNA mutants have been classi- repair disorder have been deline- cally divided into irradiation, ionis- ated, for example Bloom’s syndrome, ataxia ing irradiation, and alkylating agents. , and Fanconi’s anaemia. In each Ultraviolet irradiation and alkylating agents it was hypothesised that the under- can cause a number of specific base changes, as lying defect was an inability to repair a particu- well as cross linking bases together. Ionising lar type of DNA damage. For some of these irradiation is thought to generate the majority disorders this hypothesis was supported by of its mutational load by free radical produc- cytogenetics studies using DNA damaging tion. A wide variety of other DNA damaging agents, these tests defined the so-called chro- agents, both natural and man made, are mosome breakage syndromes. A number of the known, many are used as chemotherapeutic aetiological have recently been cloned, agents. confirming that some DNA repair disorder phenotypes can be caused by more than one DNA repair and vice versa. This review deals only with The DNA double helix seems to have evolved the more common DNA repair disorders. so that , even as small as individual Rarer entities, such as Rothmund-Thomson base damage, are easily recognised. Such syndrome and , are recognition is usually by a change to the physi- excluded. Some useful addresses are given at cal structure of the DNA double helix. A the end of the paper. number of diVerent pathways are involved in DNA repair. Furthermore, these pathways are DNA damage coordinated with other cellular functions, in DNA is continually subjected to both exog- particular gene and the . enous and endogenous mutagenesis. Cells have DNA repair pathways can be classified into built up sophisticated mechanisms to minimise four groups: (1) specific base change repair

the eVects of this. Mutations in actively mechanisms; (2) excision repair; (3) recombi- http://adc.bmj.com/ transcribed genes are preferentially repaired national repair; and (4) . and all DNA should be repaired before DNA For many individual base mutations, specific replication when a can become glycosylases have evolved to detect and remove “fixed” and be transmitted to daughter cells. the damaged base. DNA polymerase and ligase Endogenous mutagenesis is the inevitable repair the caused by the removed base. consequence of a large complex molecule The excision repair pathway has been inten- present in a metabolically active environment, sively studied and, although complex, is for example depurination (which occurs be- capable of repairing a wide variety of types of on October 2, 2021 by guest. Protected copyright. cause of the reaction of DNA in water), the DNA damage (see fig 1). Many of the eVect of oxygen and free radicals (causing base involved in excision repair have other damage and DNA strand breaks), and errors functions.3 This pathway preferentially repairs caused by DNA replication (causing base mis- actively transcribed genes, because of the tran- matches and deletions). The scale of endog- scription complex TFIIH. TFIIH is involved in enous mutagenesis is considerable. Depurina- initiating transcription but should transcription tion has been estimated to occur at a rate of halt, TFIIH can recruit excision repair pathway 10 000 bases per day per cell.1 Other DNA proteins and when the repair is complete hydrolysis reactions occur at a lesser rate, reconstitute the proteins required to continue approximately 100-fold slower than depurina- transcription. The cell has recombination tion and reactive oxygen species cause more mechanisms and these are used in meiosis, than 70 diVerent chemical alterations to DNA. mitosis, gene rearrangements, for example DNA replication has a very high fidelity, prob- antibody production, and DNA repair. Recom- ably less than one mutation per cell copied.2 bination repair is vital where both DNA strands However, occasional mistakes are made by the have been damaged, or there has been a double Department of Clinical DNA polymerases miscopying bases (despite strand DNA break. This mechanism involves Genetics, Ashley Wing, proof reading abilities) and also because the proteins which can detect free DNA strands St James’s University DNA polymerase complex skips areas of DNA (one such is DNA dependent protein Hospital, Leeds LS9 in which there is a pre-existing mutation kinase, the cause of autosomal recessive severe 7TF present. Such mutations are detected and combined immune deficiency), and recombine Correspondence to: repaired by specific postreplication repair the DNA strands and recruit the DNA Dr Woods. mechanisms. polymerase/ligase complex, as in stage 1e of DNA repair disorders 179 Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from

Figure 1 Excision repair is involved in repair of the majority of DNA mutations. Mutations in the XPA-G genes cause the various types of xeroderma pigmentosa, ERCC1 is a protein whose mutated gene causes the excision repair cross complementation group 1 cell line, RPA is which binds to single stranded DNA and DNA polymerase synthesise a new DNA strand complimentary to the template strand and DNA ligase links two deoxyribose sugars together with a phosphate group. (A) A site of a mutation in DNA is detected either by the DNA transcription complex “stalling” or by XPA and XPE detecting a conformational change in the DNA double helix. (B) The protein ERCC1 binds to XPA/XPE and recruits XPF which introduces a upstream (5') nick into the mutation bearing DNA strand (arrow). (C)XPB and XPD unwind the 5' end of the mutation bearing single stranded DNA. XPC and XPG introduces a downstream (3') nick into the mutation bearing DNA strand (arrow). (D) XPB and XPD unwind the 3' end of the mutation bearing single stranded DNA, allowing it to detach from its sister strand. RPA and other proteins stabilise and protect the resultant single stranded gap in DNA. (E) DNA polymerase E/D and other proteins repair the gap using the non-mutated sister DNA strand as a template. (F) DNA ligase links two ribose units together with a phosphate bond. (G) , other base modifciation, and tertiary structural changes then occur to yield repaired and functional double stranded DNA. http://adc.bmj.com/ excision repair. Postreplication repair occurs spectrum mirrors that seen in the normal immediately after DNA polymerase has pro- population with leukaemia developing at an duced a daughter strand. Before the newly syn- average age of 22 years and other solid thesised daughter strand is methylated, any tumours, particularly of the breast and gas- DNA mutations are detected and repaired. trointestinal tract, by 35 years.7 Germ line mutations in genes in this pathway While the diagnosis of Bloom’s syndrome cause the adult onset autosomal dominant pre- can be suspected clinically, the condition is

disposition to bowel , known as heredi- probably not characteristic enough for on October 2, 2021 by guest. Protected copyright. tary non-polyposis colon cancer.4 cytogenetic/molecular genetic confirmation to be omitted. The clinical diVerential diagnosis Bloom’s syndrome includes Dubowitz’s syndrome, Russell-Silver This condition was first described by Bloom in syndrome (including maternal chromosome 7 1954.5 In the past two decades, James German uniparental disomy), chromosome anomalies, in New York, has been the major publisher of fetal alcohol syndrome, and Rothmund- clinical and laboratory data. Thomson syndrome. In only Bloom’s syn- The principal clinical features of this condi- drome does cytogenetic analysis show a six to tion are prenatal and postnatal growth retarda- 10-fold increased rate of sister-chromatid tion, a thin triangular face and a telangiectatic exchanges (see fig 3A). The cytogenetic rash in sun exposed areas, particularly on the laboratory test for sister-chromatid exchange is cheeks (see fig 2A). Birth weight is typically simple to perform and reliable. Prenatal <2500 g at term. Postnatal growth retardation diagnosis has rarely been performed. There- results in an average adult height in males of fore, it should be carried out by a centre with approximately 151 cm and, in females, 144 cm. previous experience and with a combination of Because of the growth retardation, children techniques, that is sister-chromatid exchange may be investigated, often extensively, for rate and mutation detection or linked polymor- causes of failure to thrive.6 Fertility is normal in phic markers. females but probably all males are infertile. Bloom’s syndrome is an autosomal recessive Intelligence is normal. The major complication disorder. The condition is extremely rare, of Bloom’s syndrome is a substantially in- anecdotally less than one case per million in the creased incidence of malignancies. The cancer UK population. The exception is the 180 Woods

Ashkenazi Jewish population where the inci- pairs of DNA) was delineated. A gene within dence is one in 10 000. The gene causing this region proved to be the cause of Bloom’s Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from Bloom’s syndrome has recently been cloned syndrome, and is a member of the RecQ and is located on chromosome 15q21.3.8 The protein family, which are capable of discovery was made by the exploitation of the unwinding DNA and RNA. Another gene in increased rate of sister-chromatid exchange the same family of proteins is known to cause seen in Bloom’s syndrome. Occasional cell Werner’s syndrome (a rare recessive disorder lines were present in aVected individuals, causing growth retardation with accelerated which appeared to be “cured”. It was reasoned aging). Quite why growth retardation, in- that this was because the patient had a different creased sister-chromatid exchanges, and the mutation in each of their two Bloom genes and increased predisposition to cancer occur in that a sister-chromatid exchange had separated Bloom’s syndrome, is not yet understood. these, hence producing a “healed” gene and a gene with two mutations. Such a cell line would Ataxia telangiectasia (Louis-Bar be expected to have no increase in sister- syndrome) chromatid exchange, as this is the finding in This condition was initially reported by parents of aVected children who are obligate Madame Louis-Bar in 1941, but it was Boder carriers. By analysis of such cell lines a 2 centi- and Sedgwick in the United States, who were morgan region (approximately 2 million base responsible for bringing it to medical http://adc.bmj.com/ on October 2, 2021 by guest. Protected copyright.

Figure 2 Clinical features of DNA repair disorders. (A) Facial appearance of Bloom’s syndrome. (B) Ocular telangiectasia in ataxia telangiectasia. (C) Radial ray anomaly and unilateral microphthalmia in Fanconi’s anaemia. (D) Facial ina3yearoldAsian child living in the UK with xeroderma pigmentosa. (E) Facial appearance of Cockayne’s syndrome. DNA repair disorders 181

the diagnosis of ataxia telangiectasia should be made by a combination of clinical and labora- Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from tory investigations. While á-fetoprotein is often raised in the condition and immunoglobulins

IgA, IgG and, particularly, IgG2 and IgG4 sub- groups can be deficient, these findings are not as sensitive as cytogenetic studies and certainly not as specific. Prenatal diagnosis is available, but should only be carried out in centres with a specialist interest and previous experience. Chromosome breakage analysis at amniocentesis is reliable. Doubt remains for chorionic villus sampling; I know of one case where a false negative result was obtained. A further proviso is that prenatal diagnosis should not be performed without the radiosensitivity of the index case in the family being tested by the laboratory that will carry out the prenatal diagnosis. With the discovery of the ATM (ataxia telangiectasia mutated) gene, mutation and linkage analysis on chori- onic villus sampling tissue will probably become the prenatal diagnosis method of choice in the foreseeable future. Ataxia telangiectasia is a single gene auto- somal recessive disorder. Initial cell line fusing experiments had suggested that there would be at least four genes that could cause ataxia telangiectasia. However, this proved erroneous. Figure 3 Cytogenetic features of DNA repair disorders. (A) Lymphocyte cytogenetic preparations labelled with Linkage in ataxia telangiectasia was initially BRdU showing a harlequin pattern, characteristic of an found in a Pennsylvanian Amish family by increased rate of sister-chromatid exchanges pathognomonic Gatti et al on chromosome 11q23.11 Subse- of Bloom’s syndrome. (B) Cruciate exchange figures seen in a cytogenetic spread of an individual with Fanconi’s quent work by groups in the UK, United anaemia. States, and Israel refined the position of the gene and, eventually, found an extremely large hitherto unknown gene, which was called attention.9 Since then significant work in the ATM. 12 The gene seems homologous to a field has been performed by Richard Gatti in group of phosphatidylinositol-3 kinases in- the United States and the team of Malcolm volved in signal transduction, meiotic recombi-

Taylor in Britain. nation and cell cycle controls. Mutations in the http://adc.bmj.com/ The principal clinical features of ataxia ATM gene have been found in all of the four telangiectasia are a progressive complex neuro- apparent groups of ataxia telangiectasia. The degeneration, bulbar telangiectasia (see fig inferred function of the gene is in the 2B), variable immune deficiency, and an coordination of DNA damage repair. increased predisposition for lymphoreticular Approximately 10% of individuals with malignancies.10 The majority of children ataxia telangiectasia have a later onset and present within the first five years of life with slower disease progression of the condition; motor delay. Eye movements are usually this is known as variant ataxia telangiectasia.13 on October 2, 2021 by guest. Protected copyright. abnormal by the age of 3 years and involve a Such individuals exhibit less sensitivity to ion- dyspraxia of rapid saccadic eye movements, ising irradiation and they may be less cancer both in the vertical and horizontal fields of prone. In some cases the sensitivity to ionising vision. (A very similar eye movement disorder irradiation can only be shown in fibroblasts; is seen in Cogan’s ocular motor apraxia, but lymphocyte testing is normal. The majority of with only horizontal saccades involved.) Ap- variant ataxia telangiectasia is caused by ATM proximately a quarter of patients have clinically gene mutations. However, one Asian family has significant immunodeficiency. been described with variant ataxia telangiecta- Clinical diagnosis of ataxia telangiectasia can sia not linked to the ATM gene. be diYcult to make in the first five years of life. A comment needs to be made about the The diagnostic laboratory test is a six to 10-fold reported increased risk of cancer of ATM gene increased level of chromosome breakage, after mutation carriers (ataxia telangiectasia hetero- ionising irradiation. There is also an increased zygotes, that is parents and two thirds of the incidence of spontaneous chromosome break- siblings of aVected children). Epidemiological age and specific translocations involving the T studies had suggested that female heterozy- cell receptor genes on 7 and 14. gotes had an increased risk of developing breast These findings are not pathognomonic and are cancer. Furthermore, it was suggested that almost identical to those seen in the much rarer mammography may be deleterious in this Nijmegen breakage syndrome (autosomal re- population because of increased radiosensitiv- cessive borderline , moderate to ity. This is a vexed field but recent reanalysis of severe immune deficiency, increased incidence the British data has not shown the significant of lymphoreticular malignancies). Therefore, increased risk of breast cancer in known ataxia 182 Woods

telangiectasia heterozygotes, with a relative risk addresses). Auerbach et al have reported a large of approximately two contrasting with the ear- series using diepoxybutane.18 Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from lier American figure of six. Furthermore, ataxia There is good evidence for five separate Fan- telangiectasia heterozygotes have not been coni’s anaemia genes, named groups A to E. shown to have an adversely clinical respond to Two genes have been cloned, the first was the irradiation and only subtle experiments can Fanconi group C gene on chromosome show an increased ionising irradiation sensitiv- 9q22.3.19 Preliminary mutation analysis sug- ity in them as a group. The Department of gests that this gene accounts for 10% of cases. Health has advised that female ataxia tel- An apparently homologous gene has been angiectasia heterozygotes under the age of 50 found in mice. The second gene causes should only have mammography symptomati- Fanconi group A and accounts for about two cally. They should enter the National Breast thirds of cases.20 Studies are currently under Screening Programme at 50 and should avoid way to determine how the Fanconi’s anaemia A inessential radiography. and C gene mutations cause the disease phenotype. At present there seems no clinical diVerences between the Fanconi’s anaemia Fanconi’s anaemia genotypes. The condition was first described by Fanconi in 1927 in three siblings, who developed .14 Further work by Schroeder- Xeroderma pigmentosa, Cockayne’s Kurth and, more latterly, Auerbach, has helped syndrome, and to define the other features of the disease. The These three conditions are discussed together Estren-Dameshek syndrome of autosomal re- because of clinical similarities and that they are cessive congenital pancytopenia is part of the caused by mutations of excision repair pathway Fanconi’s anaemia spectrum. genes. In 1968 Cleaver showed that xeroderma The three cardinal features of Fanconi’s pigmentosa could be caused by a defect in anaemia are chromosome breakage, pancyto- repair of ultraviolet damaged DNA.21 His team penia, and congenital anomalies. While the has since carried out much of the fundamental chromosome breakage and probably the pan- work into this group of disorders, other impor- cytopenia are universal features of Fanconi’s tant research teams have been that of Lehmann anaemia, congenital abnormalities and dys- and Arlett in Brighton and Jaspers in the Neth- morphic features and growth retardation are erlands. not. This has lead to diYculties, both in recog- The predominant feature of xeroderma pig- nising cases where there are no or few congeni- mentosa is a much increased sensitivity to tal malformations before the onset of pancyto- ultraviolet light, present in sunlight.22 The skin penia and, conversely, failure to recognise that is normal at birth but develops progressive some children with multiple severe congenital , irregular pigmentation (for example malformations actually have Fanconi’s freckles at abnormally young ages; see fig 2D), anaemia.15 Furthermore, with regard to the telangiectasia and, later, keratoses, basal cell

congenital anomalies, not only is there an and squamous cell carcinomas. Tumours occur http://adc.bmj.com/ interfamilial variability, there is also an intrafa- by 3 or 4 years of age and most patients die of milial variability. Three useful features which malignancy in the second and third decade; help distinguish Fanconi’s anaemia from other such is the sun sensitivity that tumours of the conditions with a similar phenotype are growth tongue can occur. Other malignancies do not retardation, radial ray anomalies, and (usually occur more often than expected. unilateral) microphthalmia (see fig 2C). There A subgroup of individuals with xeroderma is an increased incidence of acute non- pigmentosa develop the de Sanctis-Cacchione lymphoblastic leukaemia with a mean age of variant,23 with progressive microcephaly, men- on October 2, 2021 by guest. Protected copyright. diagnosis at 15 years in individuals who have tal retardation, cerebellar ataxia, areflexia, not received a marrow transplantation.16 growth retardation leading to dwarfism, and The laboratory diagnosis is made by finding hypogonadism (a considerable phenotypic an increased incidence of chromosome break- overlap with Cockayne’s syndrome). age induced by alkylating agents, such as nitro- The major clinical features of Cockayne’s gen mustards, mitomycin C, and diepoxybu- syndrome are progressive leukodystrophy, pro- tane. An increased incidence of spontaneous gressive microcephaly, and progressive growth chromosome breakage is seen, as are unusual retardation. The majority of patients present cruciate exchange figures between non- between the ages of 3 and 5, often with homologous chromosomes (see fig 3B). False sensorineural deafness, initially masquerading negatives results have been described in as mild developmental delay, but later includ- Fanconi’s anaemia as have false positive results ing developmental delay. Usually at this time in some other rare syndromes.17 If there are any growth deficiency, particularly with loss of adi- doubts about the cytogenetic diagnosis a repeat pose tissue, is becoming apparent, as is a char- sample or testing of another tissue, such as acteristic facial appearance with sunken eyes skin, or use of a diVerent alkylating agent, is (see fig 2E). Other clinical features have been mandatory. recently reviewed.24 Rare cases presenting in Prenatal diagnosis is possible, but should the neonatal period (sometimes called COFS only be performed after confirming that the syndrome) and also with later onset and slow index case is sensitive to the alkylating agent to progression have been described. be used and probably with or by a centre with Trichothiodystrophy is an extremely rare previous experience (C Mathew, listed in disorder and is characterised by brittle hair, DNA repair disorders 183

, short stature and sometimes a distinctive facial appearance, microcephaly, Key messages Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from mental retardation, and sun sensitivity. The x DNA repair disorders are caused by natural history of the disorder has not been well genes involved in DNA mutation detec- documented but there does not appear to be an tion, repair, or repair coordination. Many excess of skin or other malignancies. of the genes have other cellular functions, The diagnosis of the three conditions, possibly explaining the diverse pheno- xeroderma pigmentosa, Cockayne’s syndrome, types seen in this group of disorders and trichothiodystrophy, is made by the x The disorders are individually rare and characteristic clinical features. The definitive suspected diagnoses should always con- laboratory investigations for all genotypes of firmed by laboratory tests (which are reli- xeroderma pigmentosa is the fibroblast survival able even before the full phenotype has after ultraviolet irradiation. This investigation evolved) is not routinely available in cytogenetic labora- x The disorders are autosomal recessive: tories but may be performed, after discussion prenatal diagnosis is available for most with Lehmann, Cleaver, or Jaspers. Lym- but may need to be arranged with phocyte cytogenetic studies are normal. specialist centres, before pregnancy Cockayne’s syndrome can usually be diag- x Many of the disorders are cancer prone nosed by clinical findings backed up by abnor- but, as the individuals can be hypersensi- mal investigation results, particularly basal tive to chemotherapy and radiotherapy, ganglia intracranial calcification, best detected treatment of any cancer that develops can by magnetic resonance imaging. Gene muta- be problematic tion and cellular defect tests for Cockayne’s syndrome, as outlined below, are only available via research laboratories. The diagnosis of ultraviolet irradiation but normal excision trichothiodystrophy is, again, suggested by the strand repair. Two genes can cause Cockayne’s clinical phenotype, although other disorders syndrome, have been cloned, and are involved which involve mental retardation and brittle in the coupling of transcription and repair. hair, such as argininosuccinicaciduria, Mutations in some individuals with trichothio- Menkes’ syndrome, and citrullinaemia need to dystrophy have been found in the XPD/ be considered. The specific test for trichothio- ERCC2 gene. This gene is a helicase and part dystrophy may be available via Lehmann. of the transcription factor complex TFIIH. Some cases of Pollitt’s syndrome (also known This complex is both involved in transcription as TAY, IBIDS, BIDS) who have brittle hair and the recruitment of the excision repair with low sulphur content and trichorrhexis pathway. It seems that mutations in the XPD nodosa, short stature, and mental retardation gene either aVect the excision repair pathway plus or minus ichthyosis and sun sensitivity recruitment giving rise to xeroderma pigmen- have trichothiodystrophy. tosa type D, or DNA transcription giving rise All three conditions are rare, have autosomal to trichothiodystrophy.

recessive inheritance, and are found in all racial http://adc.bmj.com/ groups, xeroderma pigmentosa being more common than Cockayne’s syndrome and the Conclusion very rare trichothiodystrophy. The primary The DNA repair disorders are clinically defects in this group of disorders involve com- diverse. Most cause growth retardation and a ponents of the excision repair pathway, as out- predisposition to malignancy, some cause neu- lined in the section on DNA repair mecha- rodegeneration and congenital anomalies. nisms. The diagnosis of an excision repair Some disorder phenotypes may be caused by defect can usually be made by measure of mutations in more than one gene. Also on October 2, 2021 by guest. Protected copyright. “unscheduled DNA synthesis”. This step of diVerent mutations in some genes can cause excision repair (shown in fig 1E) more than one disease phenotype. The major- can be assayed by the use of tritiated thymidine ity of the genes causing DNA repair disorders in place of normal thymidine in growth media have recently been cloned. As these genes of the test cells. The amount of radioactive thy- commonly have DNA repair as well as other midine incorporated into the DNA is a cellular functions and are components of com- measure of the amount of nucleotide excision plex multistep pathways this goes some way to repair that has been performed. explain the confusing number of genotypes and The majority of the eight genes causing dif- phenotypes. Work is now in progress to ferent xeroderma pigmentosa groups “A” to determine how each gene causes a particular “G” and “variant”, have been located and most phenotype and what role they may have in cloned.25 They are all highly homologous, human development and disease. either in terms of DNA sequence or function to the equivalent genes in mice, bacteria, and yeast. Cockayne’s syndrome cells are hypersen- 1 Lindahl T, Nyberg B. Rate of depurination of native deoxyribonucleic acid. Biochemistry 1972;11:3610–8. sitive to ultraviolet C light, though not as 2 Feig DI, Loeb LA. Endogenous mutagenesis. In: Eeles RA, marked as in excision repair deficiency of xero- Ponder BAJ, Easton DF, et al,eds.Genetic pre-disposition to cancer. London: Chapman and Hall, 1996: 175–85. derma pigmentosa cells. The specific defect is 3 Svejstrup JQ, Wang Z, Feaver WJ, et al.DiVerent forms of TFIIH for transcription in DNA repair. Cell 1995;80:21–8. in the preferential repair of mutations in 4 Lynch HT, Smyrk T. Hereditary non-polyposis colorectal transcribed genes, rather than in general cancer. Cancer 1996;78:1149–67. excision repair. The diagnostic findings are 5 Bloom D. Congenital telangiectatic resembling lupus erythematosus in dwarfs. Am J Dis Child 1954;88: failure of recovery of RNA synthesis, after 754–8. 184 Woods

6 German J, Bloom D, Passarge E. VIII. 25 Arlett CF, Lehmann AR. Xeroderma pigmentosa, Cockayne

Review of clinical genetic aspects. In: Goodman RM, syndrome and trichothiodystrophy: sun-sensitive to DNA Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from Motulsky AG, eds. Genetic disease among . repair defects in skin cancer. In: Eeles RA, Ponder BAJ, New Year: Raven Press, 1979: 121–39. Easton DF, et al,eds.Genetic pre-disposition to cancer. 7 German J. Bloom syndrome X. The cancer proneness points London: Chapman and Hall, 1996: 185–206. to chromsome mutation as a crucial event in human neoplasia. In: German J, eds. Chromosome mutation and neoplasia. New York: Alan R Liss, 1983: 347–57. 8 Ellis MA, German J. The molecular genetics of Bloom syn- drome. Hum Mol Genet 1996;5:1457–63. Useful addresses 9 Boder E. Ataxia telangiectasia: some historic clinical and 1. Ataxia-Telangiectasia Society, Mrs Glynis pathological observations. Birth Defects Original Article Series 1975;11:255–70. Watkins, 42 Parkside Gardens, Wollaton, Not- 10 Woods CG, Taylor AMR. Ataxic telangiectasia in the British Isles: the clinical and laboratory features of 70 aVected tingham NG8 2PQ (tel: 0115 928 7025). individuals. QJMed1992;82:169–79. 2. Dr C F Arlett and Dr A R Lehmann, 11 Gatti RA, Berkel I, Boder E. Localisation of the ataxia- MRC Cell Mutation Unit, University of telangiectasia gene to chromosome 11q22–23. Nature 1988;336:577–9. Sussex, Falmer, Brighton BN1 9RR (tel: 01273 12 Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia-telangiectasia gene with a product similar to a PI-3 678123). kinase. Science 1995;268:1749–53. 3. Dr James Cleaver, Laboratory of Radiobi- 13 Taylor AMR, Flude E, Laher B, et al. Variant forms of ataxia ology, University of California, Box 0750, San telangiectasia. J Med Genet 1987;24:6659–77. 14 Fanconi G. Familiäre infantile perniziosaartige anämie. Z Francisco, CA 94143-0750, USA (tel: +1 415 Kinderheilk 1927;117:257. 15 Kwee ML, Kuyt LP. Fanconi anaemia in the Netherlands. 476 4563). In: Schroeder-Kurth TM, Auerbach AD, Obe G, eds. Fan- 4. Dr James German, New York Blood Cen- coni anaemia. Berlin: Springer Verlag, 1989: 18–33. 16 Hebell W, Frederick W, Kohne E. Therapeutic aspects of tre, 310 E 67th Street, New York, NY 10021– Fanconi anaemia. In: Schroeder-Kurth TM, Auerbach AD, 6204, USA (tel: +1 212 570 3075). Obe G, eds. Fanconi anaemia. Berlin: Springer Verlag, 1989: 47–59. 5.DrNGJJaspers, Department of Cell 17 Woods CG, Leversa J, Rogers J. Severe intrauterine growth Biology and Genetics, Erasmus University, PO retardation and mitomycin C sensitivity; a new chromo- Box 1738, 3000 DR Rotterdam, The Nether- some breakage syndrome. J Med Genet 1995;34:203–6. 18 Auerbach AD, Ghosh R, Pollio PC, et al. Diepoxybutane test lands. for pre-natal and post-natal diagnosis of Fanconi anaemia. 6.DrCGMathew, Regional DNA Labora- In: Schroeder-Kurth TM, Auerbach AD, Obe G, eds. Fan- coni anaemia. Berlin: Springer Verlag, 1989: 71–82. tory, Division of Medical and Molecular 19 Strathdee CA, Gavish H, Shannon WR, et al. Cloning of C for Fanconi anaemia by function and complementa- Genetics, Guy’s Hospital, St Thomas’ Street, tion. Nature 1992;356:763–7. London SE1 9RT (tel: 0171 955 4648). 20 A’Andea AD. Fanconi anaemia forges a novel pathway. Nat 7. ProfessorAMRTaylor, Cancer Research Genet 1996;14:240–2. 21 Cleaver JE. Defective repair replication of DNA in Laboratories, University of Birmingham, Eg- xeroderma pigmentosa. Nature 1968;218:652–6. 22 Kramer KH, Rapini RP, Beran M. Xeroderma pigmentosa: baston, Birmingham B15 2TJ (tel: 0121 414 cutaneous, ocular, and neurological abnormalities in 830 4471). published cases. Arch Dermatol 1987:123:241–50. 8. Yorkshire Regional Genetics Service, 23 de Sanctis C, Cacchione A. L’idiozia xerodermia. Rivista Sperimentale Di Freniatria E Medicina Legale Delle Aliena- Department of Clinical Genetics, St James’s zioni Mentali 1932;56:269. 24 Nance MA, Berry SA. : a review of 140 University Hospital, Leeds (tel: 0113 206 cases. Am J Med Genet 1992;42:68–84. 5555; direct line). http://adc.bmj.com/ on October 2, 2021 by guest. Protected copyright.