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Volume 48, Issue 1, Pages 107-122 (January 2003)


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Ocular Manifestations in the Inherited DNA Repair Disorders☆

Hélène Dollfus, MD, PhDCorresponding Author Information12, Fernanda Porto, MD2, Patrick Caussade, MD, Claude Speeg-Schatz, MD, PhD2, José Sahel, MD2, Edouard Grosshans, MD3, Jacques Flament, MD2, Alain Sarasin, PhD4

Abstract 

Deoxyribonucleic acid (DNA) repair is a fundamental process designed to keep the integrity of genomic DNA that is continuously challenged by intrinsic or environmental induced alterations. Numerous genes involved in DNA repair have been cloned and are involved in different DNA repair pathways: base excision repair, nucleotide excision repair, mismatch repair, DNA recombination. Inherited conditions due to mutations in DNA repair genes include mainly: xeroderma pigmentosum, Cockayne syndrome, Trichothiodystrophy, Bloom syndrome, Rothmund-Thomson syndrome, and Werner syndrome. Minor to major ocular manifestations occur in these syndromes. For example, eyelid skin cancers in xeroderma pigmentosum and retinal dystrophy in Cockayne syndrome are major features of these syndromes. This review focuses on the DNA repair pathways, the general and ocular features of the related syndromes, the laboratory tests useful for diagnosis, and the general processes implied with DNA repair (ultraviolet sensitivity, carcinogenesis, apoptosis, oxydative stress, and premature aging).

Keywords:  base excision repair (BER), Bloom syndrome, cancer, Cockayne syndrome, cornea, cunjunctiva, DNA helicase, DNA repair, eye, mismatch repair, nucleotide excision repair (NER), premature aging, retina, Rothmund-Thomson syndrome, trichothiodystrophy, UV light, xeroderma pigmentosum, Werner syndrome

Article Outline

• Abstract

• Introduction

• DNA Repair Pathways

• DNA Repair Assays

• Inherited DNA Repair Disorders With Ophthalmic Manifestations: NER-TCR Pathways

• Xeroderma pigmentosum

• General Presentation

• Eye Manifestations

• Laboratory Diagnosis

• Molecular Diagnosis

• Management

• Cockayne syndrome

• General Presentation

• Eye Manifestations

• Laboratory Diagnosis

• Molecular Diagnosis

• Clinical Management

• Trichothiodystrophy

• General Presentation

• Eye Manifestations

• Laboratory Diagnosis

• Molecular Diagnosis

• Clinical Management

• Inherited Helicase Disorders with Ophthalmic Manifestations

• Bloom syndrome

• General Presentation

• Eye Manifestations

• Laboratory Diagnosis

• Molecular Biology

• Management

• Rothmund-thomson syndrome

• General Presentation

• Eye Manifestations

• Molecular Biology

• Management

• Werner syndrome

• General Presentation

• Eye Manifestations

• Laboratory Diagnosis

• Molecular Biology

• Management

• Conclusions

• Methods of Literature Search

• References

• Copyright

Introduction 

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Deoxyribonucleic acid (DNA) repair disorders refer to a group of conditions that are characterized by a failure of distinct cellular DNA repair mechanisms to function properly. The consequences of these failures are far reaching and extend to abnormalities related to normal growth and development, aging (normal and premature), programmed cell death (apoptosis), and uncontrolled cell proliferation (cancer)—all generalized processes which may affect the eye.31, 71, 84, 100, 122, 123, 152, 155

During life, damage to DNA may either occur spontaneously or be induced by external agents (Fig. 1).31, 84, 122, 123, 152 For example, the structure and integrity of the DNA molecules can be altered spontaneously because of intrinsic instability of chemical bonds in DNA (deamination or depurination) or endogenously through cellular metabolism involving reactive oxygen species (Fig. 1).]125 External factors such as irradiation, ultraviolet (UV) light, or chemical compounds can also alter DNA. The damaged DNA is repaired by one of several pathways, including base excision repair, nucleotide excision repair, mismatch repair, or by DNA recombination (Fig. 1).


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Fig. 1. DNA lesions and repair mechanisms. DNA damaging agents are shown at the top of the figure. The lesions they induce are indicated in the middle on the double DNA helix. The repair mechanism implied are indicated by the large arrows. Abbreviations: A = adenine; U = uracil; G = guanine; T = thymine; C = cytosine; BER = base excision repair; NER = nucleotide excision repair; CPD = cis-syn-cyclobutane diemer; 6-4PP = (6-4) pyrimidone photoproduct. (Adapted with permission of ___ from DeBoer and Hoeijmarkers.30)


Genes that code for the proteins involved in the normal DNA repair process have been identified. Alterations in a number of these genes are associated with a number of distinct clinical syndromes which may involve the eye, including xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy, Rothmund-Thompson syndrome, Werner syndrome, and Bloom syndrome.7, 17, 19, 30, 55, 56, 76, 94 Although these disorders are relatively rare, the ophthalmologist should be aware of them because of their potential serious complications. The aim of this review is to focus on these inherited disorders of DNA repair, including the description of DNA repair pathways, appropriate laboratory tests, and the clinical and pathological features of the specific condition.

DNA Repair Pathways 

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Specific and efficient DNA repair pathways operate on different types of DNA alterations (Fig. 1). The vast majority of DNA lesions are promptly corrected by DNA repair enzymes, which are constantly scanning the DNA in order to detect and replace damaged nucleotides. Although there is some overlap, one can distinguish five major repair pathways: base excision repair (BER), nucleotide excision repair (NER), transcription-coupled repair (TCR), mismatch repair (MR), and illegitimate or homologous recombination repair.122, 123, 125, 152 Several of these pathways involve helicase enzymes (helicases) in maintaining the structure of DNA during the processes of DNA transcription, replication, and repair as discussed below.

1.Base modifications are removed by BER. To date no human inherited disorder has been related to the genes involved in BER, and, therefore, this is not discussed further.

2.Nucleotide excision repair is a ubiquitous cellular process by which short, single-stranded DNA segments containing damaged nucleotides are removed from duplex DNA.31, 37, 56, 122 This pathway is capable of removing almost any type of DNA damage, including UV-induced photoproducts that create a structural distortion in the DNA duplex. The NER process involves the action of approximately 20–30 proteins in successive steps of damage recognition, local opening of the DNA double helix around the injury, and the incision of the damaged DNA strand on either side of the lesion. After excision, the resulting gap is filled in by DNA repair synthesis followed by strand ligation.

3.Transcription-coupled repair, a subgroup of NER, is specialized in the removal of DNA lesions located on transcribed strand of active genes. Blockage of the RNA polymerase II by bulky lesions is considered as a signal for rapid removal of lesions. This process is mediated by the general transcription factor TFIIH, which is needed to open up the DNA strands in preparation for the enzyme RNA polymerase II during normal transcription initiation as well as to separate DNA strands in regions that include a DNA lesion, allowing NER to take place.33, 57, 75, 77, 78, 79, 80, 81, 82, 126 A defect in one of the NER or TCR proteins is associated with xero-derma pigmentosum, Cockayne syndrome, and trichothiodystrophy.5, 7, 17, 19, 29, 30, 31, 52, 56, 76 Although the spectrum of clinical symptoms may differ widely, there is considerable overlap between these syndromes, including the ocular manifes- tations as described below.

4.Mismatch repair eliminates base-base mismatches and insertion-deletion loops which arises as a consequence of DNA polymerase slippage dur- ing DNA replication (on repetitive and non repetitive DNA).62 Germline mutations in mis- match repair genes such as hMSH2 and hMLH1 can cause hereditary non-polyposis colorectal cancer (HNPCC).106 No specific ocular manifes- tations in these patients are known to date.

5.Numerous enzymatic activities are involved in these different repair pathways. One of the most common activities is the helicase one, that is necessary to open the double helix for replication, transcription, repair and genetic recombination.41, 86, 94, 147 Two NER proteins exhibit DNA helicase activity (XP-B and XP-D) and one protein has helicase domains but no evidence of helicase activity in vitro (CSB). Mutations in these helicases are responsible for some of these diseases. Two types of xeroderma pigmentosum (XP-B and XP-D), one type of Cockayne syndrome (CS-B), and two types of trichothiodystrophy (TTD/XPB and TTD/XP-D) are the result of a defective DNA helicase.24, 25, 50, 95, 117, 123, 126, 132, 137 In addition, another type of helicase, the RECQ subclass, is involved in several autosomal re- cessive disorders that occur in association with carcinogenesis and/or premature aging, in-cluding Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome.49, 58, 65, 66, 85, 90, 94, 99, 129 The exact role of these helicases is not yet known, but they are obviously needed for a stabilization of the genome at sites where stalled replication or recombination may occur, avoiding thus any genetic instability at these sites.

DNA Repair Assays 

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Once a DNA repair disorder is clinically suspected there are several laboratory tests, which may help delineate the condition. The unscheduled DNA synthesis (UDS) and recovery of RNA synthesis (RRS) tests (Table 1) are based on the effect of UV light on cultured cells (usually fibroblasts of the patient).124, 149 The UDS test measures the post-UV unscheduled DNA synthesis reflecting the NER pathway whereas the RRS explores the TCR pathway (Table 1 and Fig. 2).

Table 1.

DNA Repair Diagnostic Testing

DNA Repair TestingClassical DNA Repair Test (UDS)Transcription Blockage Test (RRS)
MaterialFibroblast cell culture (skin biopsy)Fibroblast cell culture (skin biopsy)
MethodCells are irradiated with UV Study of the incorporation of radioactive thymidineCells are irradiated with UV Study of the incorporation of radioactive uridine
ResultsAbnormal for: Classical XP and half of TTD Normal for: XP variant Cockayne syndrome Half of TTDAbnormal for: Cockayne syndrome Classical XP Halp of TTD Normal for: XPC
RationaleVery low rate of DNA repairVery low rate of transcription even at 24 hours
CommentsComplementation group study to be doneThe study of both UDS and RRS is necessary for Cockayne syndrome molecular diagnosis

XP = xeroderma pigmentosum; TTD = trichothiodystrophy.


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Fig. 2. Left: Unscheduled DNA synthesis (UDS) levels in cells from the wild type, Cockayne syndrome, trichothiodystrophy, and various xeroderma pigmentosum complementation groups patients analyzed as described by Sarasin et al.124 Right: Recovery of RNA synthesis (RRS) levels in cells from the wild type, Cockayne syndrome, trichothiodystrophy, and XPC complementation groups patients analyzed as described by Weeda et al.149


Inherited DNA Repair Disorders With Ophthalmic Manifestations: NER-TCR Pathways 

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Xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are all inherited disorders related to the NER or TCR DNA repair pathways. Although these syndromes are distinct clinical entities, there is some overlap with regard to the clinical findings as well as the DNA repair mechanisms. The distinct clinical and molecular biological features of each syndrome are more fully described below.

Xeroderma pigmentosum 

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General Presentation 

Xeroderma pigmentosum is a DNA repair disorder related to the NER repair pathway. The condition is rare in Europe and North America but common in countries with a high level of consanguinity such as in North Africa, Japan, and the Middle East. It is an autosomal recessive disorder characterized by cutaneous photosensitivity, pigmentary changes, and a propensity for the early development of malignancies in sun exposed mucocutaneous areas, including the eye (Table 2; Fig. 3).53,64,70,14 The defect in the NER pathway and the resulting genomic instability is responsible for the photosensitivity and the high cancer incidence observed in xeroderma pigmentosum patients.10, 19, 28, 36, 38, 68, 69, 72 Most cases are symptomatic in childhood, except for an adult variant form. These symptoms include sun sensitivity, photophobia, and, in about 20% of the patients, neurological abnormalities.32, 70, 146

Table 2.

Main Clinical manifestations in Xeroderma Pigmentosum

Skin lesionsPhotosensitivity Pigmentation (freckles) Atrophic skin changes Squamous or basal cell carcinomas Malignant melanoma 2,000-fold risk to develop skin cancer on sun exposed areas
Extra ocular manifestations10- to 20-fold increase risk of developing internal cancer 18% of cases with progressive neurological anomalies (De Santis-Cacchione syndrome)
Ocular manifestationsSkin of the eyelids (lower lids +++): Pigmented atrophy, loss of lashes, ectropion, squamous and basal cells carcinomas Conjunctiva (interpalpebral fissure +++): Telangiectasia, xerosis, chronic congestion, pigmentation Cornea: Dryness, exposure keratitis, band-like nodular ketatropathy, scarring, perforation, ulceration, opacities, vascularization, pterygium Ocular surface neoplasms (limbal area +++): Squamous cell carcinoma, basal cell carcinoma, melanoma Iros (rarely affected): Stromal atrophy, iris melanoma (1 case)
Practical guidelinesMaximal protection from ultraviolet radiation, early excision of neoplasms

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Fig. 3. Xeroderma pigmentosum in a 15-year-old boy (Photographic Archives of the Strasbourg University Ophthalmology Clinic). A: Freckles, hyperpigmentation, and hyperkeratosis are noted on the skin. Notice cunjunctival hyperemia. B: Close-up photograph of the left eye's conjunctiva showing limbal dragging of hyperemic and telangiectasic conjunctiva. C and D: Squamous cell carcinoma of the right inferior lid and evolution 2 years later. E and F: Squamous cell carcinoma of the left inferior lid and after 1-year follow-up.


Eye Manifestations 

According to two different studies, 12–50% of patients have been reported with visual impairment.48, 70 The ocular tissues, which are primarily exposed to the sun, are predominately affected including the lids, conjunctiva, and cornea.

The lids are affected in more than 80% of patients with benign and malignant lesions in a high percentage of cases.48, 70 Benign lesions such as freckles or hyperpigmented spots are very frequent. Squamous and basal cell carcinomas often occur with a predilection for the lower lid.

Keratitis, band-like keratopathy, pterygium, corneal scarring and ulceration, neovascularization, and perforation occur in 17–40% of cases.48, 70 Corneal grafts have little benefit because of chronic dryness and vascularization. Malignant neoplasms of the ocular surface most often occur at the limbal area: squamous carcinomas and more exceptionally basal cell carcinomas and melanomas.54, 70, 119 Although iris involvement is rare, one case of an iris melanoma has been reported.63

Laboratory Diagnosis 

The diagnosis of xeroderma pigmentosum can be confirmed by molecular analysis carried out on skin biopsy. The skin cells are hypersensitive to UV light and are hypermutable after UV C treatment.18, 24, 132, 153 DNA repair tests after UV exposure (UDS) can be used for biological and prenatal diagnosis.113 Patients with xeroderma pigmentosum show low UDS values compared to normal (Fig. 2, left), as well as low recovery of RNA synthesis (RRS) (Fig. 2, right) except for XP-C patients in whom RRS is normal. In addition, those patients with clinical xeroderma pigmentosum and a normal UDS may be diagnosed as an xeroderma pigmentosum variant and confirmed by a higher UV-sensitivity in the presence of caffeine on a specific assay.12 The extreme severity of the disease and the absence of efficient therapy justify performing prenatal diagnosis in families at risk by measuring UV-induced UDS in trophoblasts or amniotic cells.1, 124 Other means of diagnosis include molecular biological techniques defining the complementation group followed by DNA sequencing to find the mutations on the repair gene.

Molecular Diagnosis 

The ability to restore normal function to various DNA repair-deficient cell lines leads to the discovery of eight complementation groups. Indeed, mutations in eight different genes have been reported in patients with xeroderma pigmentosum. These include genes involved in complementation groups XP-A–XP-G in the NER repair pathway. The xeroderma pigmentosum variants are deficient in the polymerase η able to allow DNA replication through DNA lesions (xeroderma pigmentosum variant).12, 18, 24, 132, 153 Thus, the diagnosis of xeroderma pigmentosum can be determined by screening for mutations in one of the DNA repair genes, when the causing mutations have already been identified in the same family.

Management 

The management of patients with xeroderma pigmentosum involves the rigorous avoidance of sunlight and any unnecessary UV exposure. Patients should be told to wear UV-blocking clothing and use sunblock on their skin. Intensive care from dermatologists, ophthalmologists, and dentists is necessary.96 The risk of ocular surface neoplasm requires early and close follow-up by the ophthalmologist with early excision of the lesions. Very protective sunglasses and dry eye treatment are prescribed.

Cockayne syndrome 

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General Presentation 

Cockayne syndrome is a DNA repair disorder related to the TCR repair pathway. It is a progressive neurological disorder characterized in infancy by growth failure (“cachectic dwarfism”) (Fig. 4A), deficient neurological development, progressive retinal degeneration, and sensitivity to sunlight (Table 3).21, 22, 102 It also occurs in several types, depending upon the gene that is mutated.104, 110 Type I, “the classical type,” has an onset in the post natal period, whereas type II, “the severe type,” occurs before birth and usually results in death by the age 6 or 7 years.98


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Fig. 4. A: 7-year-old patient with Cockayne syndrome and severe growth delay (“cachetic dwarfism”). Photosensitivity was obvious with erythema occurring after very short sun exposure (seen on the photograph above the mouth). Intracranial calcifications were present on the CT scan. Bilateral cataracts removed at the age of 3 months. The ERG showed attenuation of the scotopic and photopic responses. B: Fundus photograph of another Cockayne syndrome patient born from consanguineous parents who disclosed severe developmental delay since the age of 6 months and microcephaly. His growth and weight were markedly delayed. He presented sensorial deafness. Photosensitivity could not be assessed. Dental caries necessitated extraction of 8 teeth under general anesthesia. Absence of fixation and erratic eye movements were noticed. The fundus (B) showed a “salt and pepper” retinopathy with a pale optic disk and the ERG showed scotopic and photopic reduction. The anterior segments were normal and the child was hyperopic (+8 diopters for both eyes). The diagnosis of Cockayne syndrome was confirmed by DNA repair testing.


Table 3.

Main Clinical Manifestations in Cockayne Syndrome

Skin lesionsPhotosensitivity, loss of cutaneous fat
Neurological manifestationsMental retardation, microcephaly severe neurological progressive impairment, intracranial calcifications
Growth failureMajor “cachectic” dwarfism
Dysmorphic featuresEnophthalmos, beaklike nose, narrow mouth and chin
DeafnessSensorineural
Dental anomaliesModerate to severe caries
Ocular manifestationsStrabismus, nystagmus photophobia Anterior segment anomalies: Decreased or absent lacrimation, miotic pupils with resistance to mydriatics, cataract congenital or early senile Posterior segment anomalies: Retinal degeneration, optic atrophy

Eye Manifestations 

One of the hallmarks of Cockayne syndrome is pigmentary degeneration of the retina, first described by Cockayne in 1936; it occurs in a high percentage (60–100%) of reported case series.22, 98, 140 Most often a “salt and pepper” type fundus is noted (Fig. 4B). The fundus changes may be progressive throughout life.140 Bone spicules, typical of those found in patients with retinitis pigmentosa, have been reported in one case.140 Optic atrophy is often reported, but warrants better documentation, as optic disk pallor is common in retinal degeneration.26 One pathological case showed an accumulation of lipofuschin in the retinal pigmentary epithelium in a 4-year-old patient.83

In addition to the clinical fundus features, electroretinographic (ERG) responses are useful especially when assessing patients with a normal fundus. The ERG shows variable degrees of reduction of scotopic and photopic responses, which seem to parallel the fundus changes and the age of the patients.140

Anterior segment examination often reveals cataracts of various types, including cortical, posterior subcapsular, and nuclear (15–36% of patients).11, 39, 98, 105, 140 Cataracts noted at birth or within the first 3 years of life are a predictor of poor prognosis as is the presence of microphthalmos or iris hypoplasia.98 Enophthalmos due to the lack of subcutaneous orbital fat is common. The poor response to mydriatics may cause surgical difficulties.92

Laboratory Diagnosis 

The diagnosis of Cockayne syndrome relies on the finding that these cells are only defective in the transcription-coupled repair of the actively transcribed genes. This is in marked contrast to the findings in xeroderma pigmentosum.143 The UDS is normal in these patients, but the recovery of RRS until 24 hours after UV irradiation is deficient (Table 1 and Fig. 2).2, 55, 82, 91, 97, 124 These two assays are necessary to test for prenatal diagnosis.81, 136

Molecular Diagnosis 

Over 90% of Cockayne syndrome patients have been described to belong to two complementation groups (defined as the ability to restore normal function to various DNA repair-deficient cell lines) and are termed CS-A and CS-B.79, 82, 133 Of these, 80% have been assigned to the CS-B group and are associated with mutations in the excision repair cross-complementing group 6 gene (ERCC6/CS-B gene).76, 79 Mutations in the CKN1 gene cause CS-A in approximately 20% of patients. In addition, several patients exhibit both xeroderma pigmentosum and Cockayne syndrome syndromes (two patients are mutated in the XP-D gene, three in the XP-B gene, and six in the XP-G gene).20, 50, 117, 139, 150 Mutations in either the CS-A or CS-B gene result in a normal NER but defective repair of UV-induced damage in transcriptionally active DNA (TC-NER) explaining the sensitivity to UV light.51, 74

Clinical Management 

The clinical management of Cockayne syndrome is purely symptomatic. Parenteral nutrition is sometimes necessary to ameliorate the cachetic state of these children.

Trichothiodystrophy 

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General Presentation 

Ichthyosis (scaling of the skin) and brittle hair (high sulfur-deficient proteins) in combination with mental and physical retardation is referred to as trichothiodystrophy (Table 4, and Fig. 5).60, 61 The clinical features of trichothiodystrophy are variable although abnormalities are generally noted from birth. Photosensitivity is present in approximately 50% of cases.40 Although the cutaneous symptoms are unique for trichothiodystrophy, there is substantial clinical overlap for growth retardation between Cockayne syndrome and trichothiodystrophy. Like Cockayne syndrome, skin cancer is not an associated finding.6, 61, 78, 127

Table 4.

Main Clinical Manifestations in Trichothiodystrophy

Skin and hair lesionsCollodion baby, brittle hair and nails, ichthyosis, photosensitivity (50% of cases), lack of cutaneous fat Polarizing light microscopy of hair: “tiger tail” pattern Scanning electron microscopy of hair: Complete or incomplete absence of cuticular layer
General statureMild to severe growth retardation
Dysmorphic featuresBird like face, receding chin, beaked nose, protruding ears
Neurological manifestationsMental retardation, spasticity, tremor and ataxia, neurodysmyelination
Ocular manifestationsCataract, photophobia, decreased lacrimation, retinal degeneration (rare++), hystagmus and optic atrophy if encephalopathy
Other featuresImmunodeficiency, decreased fertility

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Fig. 5. A 9-year-old girl born from a consanguineous marriage (another sister is also affected) presenting with trichothiodystrophy syndrome. She has mild growth and mental delay. At birth she presented as a collodion baby. Her skin shows ichtyosis (A). Her vision was 6/18 for both eyes and she had bilateral zonular cataracts (B). Her hair is brittle (C) with a typical abnormal pattern seen on microscopy in polarized light (D).


Eye Manifestations 

Cataract is the main ophthalmic feature reported in trichothiodystrophy.60, 61 Most cataracts reported in the literature are described as small-punctuated opacities present throughout the lens.108, 109 We show, herein, a patient with an unusual zonular cataract (Fig. 5B). Pigmentary degeneration of the retina is rare, but it has been described in one patient with trichothiodystrophy related to an XP-D mutation.114 Nystagmus and optic disk atrophy have also been described.61 Brittle eyelashes are also a finding and may induce a keratitis because of their abnormal orientation.101

Laboratory Diagnosis 

The laboratory diagnosis of trichothiodystrophy is based on DNA testing in fibroblast cultures. UDS and RRS show various results according to the pathway involved. Grossly trichothiodystrophy patients show 50% of the wild type level (Fig. 2).132, 135, 149 Prenatal diagnosis by fetal eyebrow or hair biopsy and by UDS analysis has been reported.112, 124

Molecular Diagnosis 

Three disease-causing genes for trichothiodystrophy have been identified to date and include XP-D (most patients), XP-B (XP-D and XP-B genes are also related to xeroderma pigmentosum and xeroderma pigmentosum/Cockayne syndrome phenotypes), and the yet-uncloned gene TTD-A.5, 8, 13, 33, 34, 38, 61, 81, 88, 89, 134, 135, 149 The XP-D and XP-B genes encode the two subunits of the TFIIH complex with DNA helicase activity. This process is involved in DNA unwinding, for instance, around a damaged DNA segment or to allow the initiation of RNA transcription by the RNA polymerase II.88, 138, 145, 151 The dual role of TFIIH in transcription and repair suggests the trichothiodystrophy phenotype to be a transcription repair syndrome, similar to Cockayne syndrome. Recently, two patients with features of both xeroderma pigmentosum and trichothiodystrophy due to XP-D mutations have been reported.14

Clinical Management 

The clinical management of trichothiodystrophy is symptomatic.

Inherited Helicase Disorders with Ophthalmic Manifestations 

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Inherited DNA helicase deficiencies due to mutations on the class of RECQL helicases are autosomal recessive conditions associated with genetic instability, predisposition to cancer, and premature aging (Table 5).35, 49, 58, 65, 66, 85, 90, 94, 99

Table 5.

Inherited Disorders Related to DNA Helicases Deficiencies

SyndromePhenotypeOcular Manifestation
WernerFeatures of premature aging: greying of hair, diabetes mellitus type II, osteoporosis, atherosclerosis, cancer-prone (elevated incidence of sarcomas)Premature aging cataract
BloomImmunodeficienct, growth deficiency, photosensitivity, predisposition to cancer of all typesConjunctival telangiectasia (rare)
Rothmund-ThomsonGrowth deficiency, photosensitivity, poikiloderma, early greying and hair loss, increase in cancer incidence (osteogenic sarcomas)Juvenile cataract

Bloom syndrome 

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General Presentation 

Bloom syndrome is characterized by growth deficiency, variable degrees of immunodeficiency, and predisposition to cancers of many sites and types.42

Eye Manifestations 

Ocular findings in this condition are reported infrequently. Conjunctival telangiectasia is the only feature reported regularly.42, 121 One case of unilateral retinoblastoma was reported in a child presumed to have Bloom syndrome.45

Laboratory Diagnosis 

Multiple non-specific chromosomal breaks are observed as well as decreased IgA, IgG, and IgM.43, 44

Molecular Biology 

Bloom syndrome is due to mutations in the RECQL gene, a DNA helicase involved in DNA replication and repair.35, 65, 66

Management 

Detection of neoplasms and infectious complications are the main objectives.44

Rothmund-thomson syndrome 

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General Presentation 

Rothmund-Thomson syndrome is characterized by early poikiloderma (Figs. 6A and 6B), growth deficiency, and an increased predisposition to cancer.


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Fig. 6. A and B: Poikilderma in a young patient with Rothmund-Thomson syndrome. C and D: 55-year-old patient with Werner syndrome with premature aging features noticed since the age of 15 years. He was operated on for bilateral cataracts at the age of 28 years.


Eye Manifestations 

Bilateral cataracts have been reported to be a common ocular feature and in one series were present in 73% of patients examined.23, 27, 103, 111, 130, 131 The cataracts were reported to be bilateral, rapid in onset (usually 2 to 3 months) and subcapsular.144 However, a recent series of 41 cases has identified only two patients with cataracts.148 The absence or sparseness of eyelashes and eyebrows are common in this syndrome.4, 144 Other, less common, ocular findings include corneal scleralization, photophobia, and blue sclera. Occasionally bilateral glaucoma, retinal coloboma, and chorioretinal atrophy have been documented in isolated cases.144

Molecular Biology 

Mutations in the DNA helicase RECQL4 gene have been found in about 50% of patients with RTS.66

Management 

Early detection of osteosarcoma with baseline radiographs of the long bones after the age of 5 years is recommended as well as avoidance of sun exposure and the use of sunscreens.148

Werner syndrome 

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General Presentation 

Werner syndrome is characterized by caricatural premature aging associated with graying of the hair often before the age of 20 years (Figs. 6C and 6D). Malignancy occurs in 10% of the cases.

Eye Manifestations 

Bilateral cataracts are diagnosed at a median age of 30 years.46 These cataracts have been described as subcapsular, cortical, nuclear, zonular, or with punctate opacifications.9, 59, 67, 90, 116 Bullous keratopathy is a common postoperative complication and may necessitate penetrating keratoplasty.73, 118, 120

Laboratory Diagnosis 

Various translocation mosaicism in cultured cells of Werner syndrome patients and poor mitogenic responses to growth factors have been observed.93

Molecular Biology 

Mutations in the RECQL2 gene, encoding for a DNA helicase, are responsible for Werner syndrome.49, 94, 99, 128

Management 

The management is symptomatic with detection of premature arteriosclerosis, osteoporosis, and cancer.

Conclusions 

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It is now well recognized that cells can tolerate exogenous and endogenous DNA lesions because of specific and efficient repair mechanisms. Alterations in a specific repair pathway, such as NER, TCR, or defects in some helicase, are known to be associated with generalized cellular processes such as UV sensitivity, cell death, premature aging, and uncontrolled cell proliferation (cancer) which are characteristic of the various syndromes described herein Fig. 7 and Table 6).5, 34, 51, 74, 94, 132, 151, 153


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Fig. 7. Schematic representation of the clinical and genetic heterogeneity in patients afflicted by xeroderma pigmentosum, Cockayne syndrome, and xeroderma pigmentosum/Cockayne syndrome or trichothiodystrophy syndromes. The overlaps between the three diseases indicate that specific mutations on the NER XP-B, XP-D or XP-G gene can produce different clinical phenotypes. The TTD-A gene is the only gene that is not cloned yet.


Table 6.

Main Clinical Manifestations in Xeroderma Pigmentosum (XP), Cockayne Syndrome (CS), and Trichothiodystrophy (TTD)

XPCSTTD
Skin and hair
Photosensitivity++++/−
Skin cancer++−−
Abnormal skin pigmentation+−−
Sulfur deficient brittle hair−−++
Eyes and lids
Cataract−++/−
Retinal Dystrophy−+rare
Photophobia+−+/−
Optic pallor/atrophy−+rare
Dry eye++/−+/−
Ocular Tumors++−−
CNS
Mental retardation+/− (20%)+++/−
Microcephaly−+++/−
Sensorineural deafness−++/−
Ataxiarare++/−
Spasticityrare++/−
Other
Growth retardation−+++/−
Sexual immaturity−++/−
Bird-like facies−++/−

UV sensitivity is a predominant feature of pure NER pathway deficiencies as in xeroderma pigmentosum.64, 68, 69, 70, 72 The spectrum of ultraviolet light may be divided into UV-A (wavelength 320–400 nm), which represents 95% of the UV received at the earth's surface. Exposure to this wavelength accounts for approximately 25% of the skin cancers. Conversely, UV-B (wavelength 280–320 nm) accounts for approximately 5% of the spectrum, but 75% of the skin cancers.142 UV-A and UV-B do not induce the same alterations at the level of DNA. UV-A produces primarily oxidative changes whereas UV-B produces lesions between adjacent pyrimidines, which are repaired by the NER pathway.142 These findings explain the prominence of ocular surface lesions in xeroderma pigmentosum as there is low passage of UV-B through the cornea and the predominance for cutaneous photosensitivity, skin conditions related to sun exposure, and skin cancer.115 Conversely, it also helps to explain the usual absence of premature cataract and retinal degeneration in these patients.

Cell death has been shown to be related to the pathogenesis of Cockayne syndrome. Indeed, the arrest of transcription provides a strong signal for a cell death pathway, and the Cockayne syndrome could thereafter be characterized as a disease of excessive death by apoptosis. In addition to the UV hypersensitivity, endogenous oxidative DNA damage is implicated in Cockayne syndrome. Lepage et al demonstrated that the common problem in cells from patients with Cockayne syndrome is a failure to repair oxidation-induced damage to DNA that is being transcribed into RNA.74 Cells from patients with Cockayne syndrome show a failure to repair oxidation-induced damage to DNA as well as the free radical-induced 8 oxoguanine lesion when located on the DNA strand that is being transcribed into RNA.74 This mechanism, and the fact that neurons rapidly generate high level of reactive oxygen species, could explain the findings of stunted growth, neurological deterioration, and the non-predisposition to cancer, as dead cells do not form tumors.51

Oxidative stress has been implicated in numerous neurodegenerative diseases.47, 154 Oxidative stress may also be important in retinal degeneration and may explain this frequent feature in patients with Cockayne syndrome.3, 15, 16, 87 It may play a role in ocular disorders including retinitis pigmentosa and age-related macular degeneration. The photoreceptors may be more vulnerable to random biochemical insults than are other retinal cells because of their high metabolic activity reflected by the large number of mitochondria and oxygen consumption.141 The retinal degeneration found in Cockayne syndrome indicates that normal cellular metabolism may lead to oxidative damage. These lesions would accumulate and produce the described retinal lesions.107

Histopathology of an eye from a Cockayne syndrome patient with “salt and pepper” retinopathy showed notable retinal pigment epithelial changes associated with lipofuschin deposition and photoreceptor loss.83 In this context, there is evidence that lipofuschin is derived, at least in part, from oxidatively damaged photoreceptor outer segments. Congenital or early childhood cataracts occur frequently in Cockayne syndrome indicating the potential role of oxidative stress in their genesis.

Premature aging is the main feature of Werner syndrome recognized as a natural model for human aging.90, 91, 92, 94, 95, 96, 97, 98, 99 The premature onset of age-related phenotypes include atherosclerosis, osteoporosis, cancer, and posterior subcapsular cataracts. The WRN gene codes for a DNA helicase belonging to the RECQ family like the Bloom or the Rothmund-Thomson proteins. However, the WRN helicase exhibits specific enzymatic activities that the two other helicases do not show (exonuclease activity and structural specificities), which may explain the absence of premature aging in Bloom syndrome and Rothmund-Thomson syndrome.128

Uncontrolled cell proliferation is the basis of carcinogenesis. Genomic instability, which can be related to DNA repair deficiencies, is a well-recognized carcinogenesis factor. Cells with RECQ helicase defect have an unstable genome, which may explain the elevated risk of cancer in the corresponding patients (Werner syndrome risk for soft tissue sarcoma, Bloom syndorme for leukemia, Rothmund-Thomson syndrome for skin cancer and osteosarcoma).

The inherited DNA repair syndromes are important for the ophthalmologist to recognize and identify because they are often associated with ocular complications. Specific laboratory tests and mutation screening may help separate these entities because there is often clinical overlap. Although each of these disorders is uncommon, they are important to study because they provide insight into the most fundamental processes associated with the cell cycle. The study of these disorders will help understanding the basic pathologic mechanisms involved in diverse processes such as premature aging and degeneration to uncontrolled cellular proliferation.

Methods of Literature Search 

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References for this review were identified through a comprehensive literature search of the electronic PUBMED database (1966–2001) and included where appropriate. Additional articles, textbooks, and abstracts that were unavailable on electronic archives were selected from review of the bibliographies of the articles generated from the above search. The OMIM database was used to complete our search. The following key words and combinations were used in compiling the search: DNA damage, DNA repair, NER, BER, TCR, DNA helicase, Mismatch repair, Cockayne syndrome, Trichothiodystrophy, Xeroderma pigmentosum, Werner syndrome, Rothmund Thomson syndrome, eye, lid, conjunctiva, eyelid cancer, sun, UV, iris, lens, cataract, retinal degeneration, oxidative stress.53

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1 Fédération de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

2 Clinique Ophtalmologique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

3 Clinique de Dermatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

4 Laboratory of Genetic Instability and Cancer, UPR2169 - CNRS, Villejuif, France

Corresponding Author InformationReprint address: Hélène Dollfus, Fédération de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, BP 426, 67091 Strasbourg cedex, France

☆ The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

PII: S0039-6257(02)00400-9


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