Ophthalmic Manifestations and Histopathology of Xeroderma Pigmentosum: Two Clinicopathological Cases and a Review of the Literature

doi:10.1016/j.survophthal.2011.03.001

Survey of Ophthalmology

Volume 56, Issue 4, July–August 2011, Pages 348-361

https://doi.org/10.1016/j.survophthal.2011.03.001 Get rights and content

Abstract

Xeroderma pigmentosum is a rare, autosomal recessive disease caused by a defect in DNA repair. Patients with xeroderma pigmentosum often have cutaneous and ocular sun sensitivity, freckle-like skin pigmentation, multiple skin and eye cancers, and, in some patients, progressive neurodegeneration. Xeroderma pigmentosum predominantly affects the ultraviolet (UV) exposed ocular surface, resulting in eyelid atrophy and cancers, corneal dryness, exposure keratopathy, and conjunctival tumors. We report the clinical history and ocular pathology of two white women who had xeroderma pigmentosum with neurological degeneration: Case 1 (died at age 44 years) and Case 2 (died at age 45 years). Case 1, with mutations in the XPA gene, had more than 180 basal cell carcinomas of her skin and eyelids and died from complications of neurodegeneration. Case 2, with mutations in the XPD gene, was sun-protected and had three skin cancers. She died from complications of neurodegeneration and pneumonia. Both patients had bilateral pinguecula, corneal pannus, and exposure keratopathy. Case 1 had bilateral optic atrophy, and Case 2 had bilateral peripheral retinal pigmentary degeneration. Both patients developed retinal gliosis. The ophthalmic manifestations and pathology of xeroderma pigmentosum are discussed and reviewed with respect to this report and other cases in the literature. These cases illustrate the role of DNA repair in protection of the eyes from UV damage and neurodegeneration of the retina.

Section snippets

Clinical History

This 44 year-old white woman with a mutation in the XPA DNA repair gene75, 76 was followed at the National Institute of Health (NIH) Clinical Center since age 4 years. From 1976 to 1992, she had 166 histologically documented basal cell carcinomas, most of which were on her face (cheeks, lips, nose, eyelids, eyebrows, and canthus). She had no squamous cell carcinomas or melanomas (Fig. 1A). During treatment with oral 13-cis-retinoic acid, from 1984 to 1986 the frequency of new basal cell

Systemic features and genetics of XP

XP is an autosomal recessive disease of defective DNA repair that affects males and females equally and is frequently symptomatic in childhood.15, 24, 49 Defects in nucleotide excision repair can lead to three diseases: XP, Cockayne syndrome, and trichothiodystrophy. XP and Cockayne syndrome both present with photosensitivity and progressive neurological degeneration.⁶⁷ XP has a greatly increased risk of sun-induced cancers, and Cockayne patients have normal cancer risk. Retinitis pigmentosa

Method of Literature Search

The literature selection for this review included a Medline database search from 1965 to June 2010 of publications in the English language. Searches were conducted with the headings xeroderma pigmentosum, ocular pathology, ocular tumor, melanoma, carcinoma, eyelid, ciliary body, cornea, iris, conjunctiva, and treatment. Articles populated under ‘Related citations’ from these articles were reviewed. Additional articles and textbooks were selected from the bibliographies of the references.

Disclosure

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. Publication of this research was supported by the Howard Hughes Medical Institute, the Intramural Research Programs of the National Eye Institute, and the Center for Cancer Research of the National Cancer Institute, National Institutes of Health.

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Müller glial cells (MC) support various metabolic functions of the retinal neurons, and maintain the homeostasis. Oxidative stress is intensified with aging, and in human retina, MC and photoreceptors undergo lipid peroxidation and protein nitration. Information on how MC respond to oxidative stress is vital to understand the fate of aging retinal neurons. This study examined age-related changes in MC of donor human retina (age: 35–98 years; N = 18 donors). Ultrastructural and immunohistochemical observations indicate that MC undergo gliosis and increased lipid peroxidation, and show osmotic changes with advanced aging (>80 years). Photoreceptor cells also undergo oxidative-nitrosative stress with aging, and their synapses also show clear osmotic swelling. MC respond to oxidative stress via proliferation of smooth endoplasmic reticulum in their processes, and increased expression of aquaporin-4 in endfeet and outer retina. In advanced aged retinas (81–98 years), they showed mitochondrial disorganisation, accumulation of lipids and autophagosomes, lipofuscin granules and axonal remnants in phagolysosomes in their inner processes, suggesting a reduced phagocytotic potential in them with aging. Glutamine synthetase expression does not alter until advanced aging, when the retinas show its increased expression in endfeet and Henle fiber layer. It is evident that MC are vulnerable with normal aging and this could be a reason for photoreceptor cell abnormalities reported with aging of the human retina.
Ocular and Periocular Tumors in Xeroderma Pigmentosum: A Study of 120 Asian Indian Patients
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We studied the incidence, treatment, and outcome of ocular and periocular tumors in patients with xeroderma pigmentosum (XP).
Retrospective case series.
This single-institution study included 120 patients with XP who underwent intervention with excisional biopsy, enucleation, or orbital exenteration. The primary outcome measures were the occurrence of eyelid or ocular surface tumor, globe salvage, locoregional and systemic metastasis, and death.
The mean age at presentation was 19 years. A family history of XP was present in 32 (27%) patients. Over a mean follow-up of 61 months, 34 (28%) patients developed no ocular/adnexal tumor, 86 (72%) developed ocular surface malignancy, 15 (13%) developed eyelid malignancy, and 22 (18%) developed other head and neck malignancies. Of the 86 patients with ocular surface malignancy, 48 (56%) had unilateral tumor and 38 (44%) had bilateral tumors. Invasive squamous cell carcinoma (n = 51, 41%) was the most common ocular surface tumor. Of the 15 patients with eyelid tumors, 14 (93%) had unilateral tumor and 1 (7%) had bilateral involvement. Basal cell carcinoma (n = 8, 50%) was the most common eyelid tumor. There were events of ocular surface tumor recurrence (n = 55 eyes, 44%), eyelid tumor recurrence (n = 5 eyes, 31%), locoregional lymph node metastasis (n = 3, 2%), systemic metastasis (n = 1, 1%), and death (n = 1, 1%). Overall, globe salvage was achieved in 119 (99%) patients (both eyes were salvaged in 92 [76%] patients and at least 1 eye was salvaged in 27 [23%] patients).
XP is frequently associated with ocular surface, eyelid, and other head and neck malignancies. Lifelong follow-up is mandatory in these patients.
Xeroderma pigmentosum
2018, Annales de Dermatologie et de Venereologie
Le xeroderma pigmentosum (XP) est une génodermatose qui se manifeste par des altérations cutanées et oculaires photo-induites et des cancers cutanés. À ces manifestations s’associe parfois une atteinte neurologique. Cette pathologie est liée à un défaut dans les gènes du système de réparation par excision-resynthèse des nucléotides (nucleotide excision repair, NER) pour les sept premiers groupes génétiques (A–G), et à une anomalie des gènes de la transcription pour le huitième groupe (xeroderma pigmentosum variant, XPV). Les carcinomes cutanés représentent les cancers les plus fréquents. Ils peuvent débuter dès l’enfance. Les mélanomes sont souvent multiples au cours du XP. Leur incidence est sous-estimée étant donné la fréquence des régressions spontanées. L’aspect clinique est caractérisé par un polymorphisme lésionnel avec une dyschromie caractéristique. Il permet dans la majorité des cas de poser le diagnostic. L’étude des capacités de resynthèse de l’ADN (unscheduled DNA synthesis, UDS) et la survie cellulaire après irradiation aux ultraviolets (UV) représentaient l’examen de référence pour le diagnostic biologique. Elles tendent actuellement à être supplantées par les nouvelles techniques de biologie moléculaire recherchant les mutations génétiques de la maladie. Ces techniques sont devenues très utiles pour l’identification des patients hétérozygotes et le diagnostic anténatal. La photoprotection est la mesure préventive essentielle. Les patients doivent éviter toute exposition aux rayons solaires et aux sources artificielles émettant des UV. Plusieurs moyens thérapeutiques modernes viennent enrichir l’arsenal thérapeutique pour détruire les tumeurs cutanées comme l’imiquimod et la photothérapie dynamique (PDT). Ces moyens sont intéressants pour éliminer les tumeurs débutantes tout en préservant la peau saine. La chirurgie et la cryochirurgie sont les moyens les mieux adaptés pour traiter les tumeurs cutanées chez ces enfants. La chimiothérapie pourrait être une alternative pour les traitements des kératoacanthomes et des carcinomes spinocellulaires (CSC). La cryochirurgie peut être associée à d’autres thérapeutiques pour détruire les CSC de l’hémilèvre. La prise en charge de ces patients dans des centres de référence, ainsi que l’intervention des associations pour soutenir les familles, ont permis d’améliorer la qualité de la prise en charge et de ralentir l’évolution de la maladie.
Xeroderma pigmentosum (XP) is a form of general dermatosis characterised by photo-induced cutaneous-ocular impairment and by skin cancers. In addition to these signs, there may also be neurological involvement. This disease is related to a defect in genes within the nucleotide excision repair system for the first seven genetic groups (A–G), and to an abnormality in transcription groups for the eighth group (xeroderma pigmentosum variant - XPV). Cutaneous carcinomas are the most common types of cancer seen. They may begin in childhood. Multiple melanoma commonly occurs during the course of XP but given the frequency of spontaneous regression, the incidence is underestimated. The clinical appearance is characterised by polymorphous lesions with characteristic dyschromia and in most cases it is sufficient to establish the diagnosis. Investigation of unscheduled DNA synthesis (UDS) and cell survival following ultraviolet (UV) radiation were formerly considered the reference examination for laboratory diagnosis. However, these tests are now being replaced by new molecular biology techniques to screen for the genetic mutations characteristic of the disease. These techniques have proved extremely useful in identifying heterozygous patients and in antenatal diagnosis. Photoprotection is the key preventive measure: patients must avoid all exposure to the sun and to artificial sources of UV radiation. The therapeutic arsenal has recently been enriched by several modern therapeutic methods used to destroy cutaneous tumours such as imiquimod and photodynamic therapy (PDT). These approaches are valuable since they eliminate incipient tumours while sparing healthy skin. Surgery and cryosurgery are the most suitable methods for treating cutaneous tumours in children. Chemotherapy may be considered an alternative for the treatment of keratoacanthomas and squamous cell carcinomas (SCC). Cryosurgery may be combined with other therapeutic approaches to eliminate SCC of the lip. Management of these patients in reference centres, coupled with assistance from associations providing support for patients’ families, has resulted in improved quality of therapy while slowing down disease progression.
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Citation Excerpt :
Notably however, none of our patients had any manifest optic atrophy. Although neurodegeneration is recognized in a significant proportion of XP patients in the literature,1,2,4,6,16 reports of specific neuro-ophthalmic changes, such as ours, remain limited.22 Most of the patients in our study had good visual function.
To document the ocular manifestations of xeroderma pigmentosum (XP), presenting via the United Kingdom (UK) XP service, and to analyze the correlations between XP genotype and ophthalmic phenotype.
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Eighty-nine patients seen by the UK Nationally Commissioned XP Service, from April 2010 to December 2014, with a genetically confirmed diagnosis of XP.
Patients underwent a full ophthalmic examination at each visit. Clinical features from both eyes were recorded on a standard proforma. The most recent assessments were analyzed. A 2-tailed Fisher exact test was used to assess for differences in ocular features between patients in XP subgroups with impaired transcription coupled nucleotide excision repair (TC-NER) (category 1: XP-A, B, D, F, and G) and preserved TC-NER (category 2: XP-C, E, and V).
Lid and periocular abnormalities, ocular surface pathologies, neuro-ophthalmologic abnormalities, lens and retinal abnormalities, and visual acuity (VA).
Ninety-three percent of XP patients in our cohort had ocular involvement, with 65% describing photophobia. The most common abnormalities were in the periocular skin and ocular surface, including interpalpebral conjunctival melanosis (44%) and conjunctival injection (43%). Eleven percent of patients had required treatment for periocular cancers and 2% for ocular surface cancers. The most common neuro-ophthalmologic finding was minimal pupillary reaction to light (25%). Patients in category 2 had significantly more ocular surface abnormalities than patients in category 1, including a greater proportion of conjunctival injection (P = 0.003), conjunctival corkscrew vessels (P < 0.001), corneal scarring (P = 0.01) and pingueculae under the age of 50 (P = 0.02). Meanwhile, patients in category 1 had a higher proportion of poorly reactive pupils (P < 0.001) and abnormal ocular movements (P = 0.03) compared with those in category 2. Five patients (6%) presented to ophthalmologists with ocular surface signs related to XP, before any formal diagnosis of XP was made.
A large proportion of XP patients have ocular involvement. Regular examination by an ophthalmologist is essential, especially in screening for eyelid and ocular surface tumors. The ocular phenotype–genotype segregation within XP patients suggests that XP is a heterogeneous and complex disease. With further study, we hope to offer these patients more individualized patient care.
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: We acknowledge our patients and their families for their contributions to our research. Drs. Jinping Lai and Yen-Chun Liu of the Laboratory of Pathology, NCI, performed the autopsies of the XP patients under supervision of Drs. David Kleiner and Carl Oberholtzer. We thank the NIH library staff for making this type of comprehensive literature search possible.

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Clinical Pathologic ReviewsOphthalmic Manifestations and Histopathology of Xeroderma Pigmentosum: Two Clinicopathological Cases and a Review of the Literature

Abstract

Section snippets

Clinical History

Systemic features and genetics of XP

Method of Literature Search

Disclosure

Exp Eye Res

J Oral Maxillofac Surg

Ophthalmology

Surv Ophthalmol

Am J Ophthalmol

Med Hypotheses

J Pediatr

Mutat Res

Int J Radiat Oncol Biol Phys

J Am Acad Dermatol

DNA Repair (Amst)

Neuroscience

Eur J Paediatr Neurol

J Am Acad Dermatol

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Surv Ophthalmol

J Pediatr

Ann Dermatol Venereol

Xeroderma pigmentosum neurological abnormalities correlate with colony-forming ability after ultraviolet radiation

Proc Natl Acad Sci USA

Neurological symptoms and natural course of xeroderma pigmentosum

Brain

Conjunctival malignant melanoma with xeroderma pigmentosum

Ophthalmologica

Ocular manifestations of xeroderma pigmentosum in a black family

Arch Ophthalmol

van Voorst Vader PC. Xeroderma pigmentosum and keratoconus

Doc Ophthalmol

Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair

J Med Genet

Grading of corneal and conjunctival staining in the context of other dry eye tests

Cornea

Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients

Proc Natl Acad Sci USA

Normal pressure hydrocephalus. Recognition and relationship to neurological abnormalities in Cockayne’s syndrome

Arch Neurol

Management of corneal complications in xeroderma pigmentosum

Cornea

Exuberant epibulbar tumor penetrating into the orbit in xeroderma pigmentosum

Graefes Arch Clin Exp Ophthalmol

Keratoacanthoma of the conjunctiva complicating xeroderma pigmentosum

Indian J Dermatol Venereol Leprol

Defective repair replication of DNA in xeroderma pigmentosum

Nature

Xeroderma pigmentosum variants have decreased repair of ultraviolet-damaged DNA

Nature

Genetic heterogeneity of xeroderma pigmentosum demonstrated by somatic cell hybridization

Nat New Biol

Xeroderma pigmentosum: spinal cord astrocytoma with 9–year survival after radiation and isotretinoin therapy

J Cutan Med Surg

Hamartomas of the iris and ciliary epithelium in tuberous sclerosis complex

Arch Ophthalmol

Xeroderma pigmentosum. I. A clinical study of 12 Egyptian cases

Br J Dermatol

Ocular manifestations of xeroderma pigmentosum

Br J Dermatol

Xeroderma pigmentosum. A report of further six cases

J Egypt Med Assoc

Limbal stem cell deficiency and xeroderma pigmentosum: a case report

Eye (Lond)

Xeroderma pigmentosum and band-shaped nodular corneal dystrophy

Br J Ophthalmol

Corneal transplantation with associated histopathologic description in xeroderma pigmentosum occurring in a black family

Ann Ophthalmol

Ocular lesions in xeroderma pigmentosum;a case report of carcinoma of the cornea

Arch Ophthalmol

Oculocutaneous manifestations in xeroderma pigmentosa

Br J Ophthalmol

Clinical Pathologic Reviews
Ophthalmic Manifestations and Histopathology of Xeroderma Pigmentosum: Two Clinicopathological Cases and a Review of the Literature