Clinical Diagnosis and Management of Xeroderma Pigmentosum and Related Disorders
Submitting InstitutionUniversity of Sussex
Unit of AssessmentBiological Sciences
Summary Impact TypeHealth
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology, Genetics
Medical and Health Sciences: Neurosciences
Summary of the impact
Individuals with Xeroderma pigmentosum (XP) are extremely susceptible to
sunlight-induced skin cancers and, in some cases, develop neurological
problems. Alan Lehmann has developed a cellular diagnostic test for this
disorder. This test is now conducted as an integral part of a
multi-disciplinary XP specialist clinic in London, which was established
as a direct result of Alan Lehmann's research in Sussex and which has led
to the improved diagnosis and management of the disorder and an improved
quality of life for affected individuals.
The cellular and molecular basis of XP and the related disorders —
Cockayne Syndrome (CS) and trichothiodystrophy (TTD) — has formed a major
part of Lehmann's research over many years. This work started at Sussex in
1975 and has continued up to the present time. His group first showed that
the variant form of XP was deficient in the ability to replicate
UV-damaged DNA and that CS cells failed to restore RNA synthesis after
UV-irradiation, leading to the discovery of a defect in
transcription-coupled repair in this disorder. TTD cells, like XP cells,
were shown to be defective in the ability to remove UV photoproducts from
cellular DNA. Based on the cellular deficiencies in DNA repair in these
disorders, elucidated in his and other labs, Lehmann developed cellular
tests specifically for diagnostic purposes [see Section 3, R1].
More recently his research progressed to analysing the genes involved in
these disorders and identifying the causative mutations in many affected
patients. Defects in any of eight different genes can result in XP.
Initially Lehmann focused on the XPD gene, defects in which can
result in a wide variety of phenotypes, namely XP, TTD, XP with CS, and XP
with TTD. Mutations in this gene were identified in patients with TTD [R2]
or XP [R3]. The important conclusion from these studies was that the exact
site of the mutation determined the clinical phenotype. Mutation analysis
was next conducted on the POLH gene defective in XP variants, and
mutations were identified both in the catalytic part of the Polf068
protein and in the C-terminal extension affecting protein localisation
Patients defective in the XPA gene are generally extremely
severely affected with both skin and neurological abnormalities. A
60-year-old XP-A patient with mild skin symptoms and no neurological
problems was found to have a mutation resulting in the abnormal splicing
of the XP mRNA. However, a small amount of normal splicing was observed
and the resulting minimal residual repair was sufficient to prevent the
onset of neurological problems [R5]. This mutation was subsequently found
in several XP patients and enabled an optimistic prognosis to be made in
these individuals. More generally, the mutation analyses have resulted in
more accurate prognoses, ascertainment of carrier status in affected
families, and improved prenatal diagnoses.
References to the research
R1 Lehmann, A.R., Thompson, A.F., Harcourt, S.A., Stefanini, M.
and Norris, P.G. (1993) `Cockayne's Syndrome: correlation of clinical
features with cellular sensitivity of RNA synthesis to UV-irradiation', Journal
of Medical Genetics, 30(8): 679-682.
R2 Broughton, B.C., Steingrimsdottir, H., Weber, C. and Lehmann,
A.R. (1994) `Mutations in the xeroderma pigmentosum group D DNA repair
gene in patients with trichothiodystrophy', Nature Genetics, 7(2):
R3 Taylor, E.M., Broughton, B.C., Botta, E., Stefanini, M.,
Sarasin, A., Jaspers, N.G.J., Fawcett, H., Harcourt, S.A., Arlett, C.F.
and Lehmann, A.R. (1997) `Xeroderma pigmentosum and trichothiodystrophy
are associated with different mutations in the XPD (ERCC2)
repair/transcription gene', Proceedings of the National Academy of
Sciences of the USA, 94(16): 8658-8663.
R4 Broughton, B.C., Cordonnier, A., Kleijer, W.J., Jaspers, N.G.,
Fawcett, H., Raams, A., Garritsen, V.H., Stary, A., Avril, M.F., Boudsocq,
F., Masutani, C., Hanaoka, F., Fuchs, R.P., Sarasin, A. and Lehmann, A.R.
(2002) `Molecular analysis of mutations in DNA polymerase eta in xeroderma
pigmentosum-variant patients', Proceedings of the National Academy of
Sciences of the USA, 99(2): 815-820.
R5 Sidwell, R.U., Sandison, A., Wing, J., Fawcett, H.D., Seet,
J.E., Fisher, C., Nardo, T., Stefanini, M., Lehmann, A.R. and Cream, J.J.
(2006) `A novel mutation in the XPA gene associated with unusually mild
clinical features in a patient who developed a spindle cell melanoma', British
Journal of Dermatology, 155(1): 81-88.
Outputs can be provide by the University on request.
Details of the impact
Xeroderma pigmentosum (XP), Cockayne Syndrome (CS) and
trichothiodystrophy are genetic disorders caused by a deficiency — in
affected individuals — in the ability to repair damage produced in
cellular DNA by ultraviolet light. Although these disorders have a
devastating effect on the affected families, in many cases, access to
clinical needs have been unsatisfactory due to a lack of clinical
expertise. Consequently, Lehmann played an instrumental role in
establishing a multi-disciplinary clinic to alleviate this problem,
initially in Worthing with Dr Arjida Woollons (an MD who trained in
Lehmann's laboratory) but, since 2008, in London, under the clinical
leadership of Dr R Sarkany [see Section 5, C1: Letter from Dr Sarkany —
`The Department of Health team (NCG) who annually audit the Service, has
commented in each audit on the excellent and symbiotic relationship
between Prof. Lehmann's team of research scientists and our
multidisciplinary clinical team, which contributes to the standard of
patient care in this Clinical Service'].
Since April 2010, following the receipt of funding from the NHS National
Commissioning Group (NCG), the clinic takes place every two weeks at St
Thomas' Hospital [C2]. Three or four patients spend the whole day at the
clinic and receive detailed examination and advice from different
specialists. Almost all (approximately 90 per cent) XP patients in this
country are now seen at this clinic, which Lehmann attends as Consultant
Scientist and where he provides genetic expertise and guidance. This has
led to improved patient management and quality of life, as indicated by
the questionnaires completed by each patient, detailing patient
satisfaction (e.g. `The whole service was excellent. Could not fault it')
and the report from the clinic to the NCG [C3, C4]. The attendance of
patients at the XP clinic has resulted in improved photoprotection,
especially for children. In 60-75 per cent of families with XP children,
the patients wear a UV-protective visor, and UV-protective film has been
installed in both home and school. Skin cancers are identified and excised
at a very early stage. There is also an increased awareness of the
importance of eye photoprotection.
As part of this clinic, Lehmann conducts diagnostic testing in Sussex
using simple assays based on his underpinning research into DNA repair
[see Section 3, R1 and Section 5, C5, C6]. These tests provide unambiguous
confirmation or exclusion of the clinical diagnoses, which has been vital
for patient management, both within the clinic and externally, worldwide.
For example, he received over 300 samples in the current REF period
(2008-2013), from which he has diagnosed about 60 positive cases of XP, CS
or TTD. His tests are also used for prenatal diagnoses and, to date, he
has carried out over 70 prenatal diagnoses in families with CS, including
10 in the current REF period. Professional/end-users who can corroborate
the impact of his input are listed below. A letter from the founder of the
XP patient support group says: `...As the Group grew it was quite clear
that level of care received by families was not consistent and care seemed
to range from negligent to excellent. We soon realised that a minimum
standard of care was needed for all XP Patients and with the help of Dr
Arjida Woollens and Professor Lehmann, an experimental Multi-disciplinary
team was set up at Southlands Hospital. The patient experience was
excellent'...The patient satisfaction questionnaires show that the service
is very well received...' [C7]. It also attests to the impact on patients
and their families by describing how Professor Lehmann "has brought the
science to our families and made us more connected with what is going on
with our children" [C7].
Sources to corroborate the impact
C1 Letter from Dr Sarkany (available on request)
C2 Hospital websites:
XP support group website: http://xpsupportgroup.org.uk/?page_id=9
C3 Patient questionnaires detailing patient satisfaction with the
C4 National Specialised Commissioning Highly Specialised Services
C5 Referral letters from clinicians (available on request)
C6 Diagnostic results letters to clinicians
C7 Individual users who could be contacted by the REF team to
- Head of the National (NCG) Xeroderma pigmentosum Clinical Service, St
Thomas' Hospital, London.
- Letter from Trustee and Founder of the XP Support Group.