Chapter 139. Hereditary Disorders of Genome Instability and DNA Repair

Because the genome exerts control for cellular function, maintaining genome stability is important for the continued function of cells, tissues, and organisms. DNA is the carrier of genetic information. Its structure is regularly threatened by damaging agents that include oxidative stress, ultraviolet (UV) and X-radiation, and chemical agents. Although much damage is repaired, failure to maintain genomic integrity may lead to abnormal cell function or cell death. If the cell divides, progeny may accumulate additional damage and this progressive accumulation of damage can lead to malignancy (see Chapter 110).

This chapter describes the relevant skin disorders with genome instability and the underlying defective mechanisms of DNA repair or DNA maintenance (Tables 139-1 and 139-2). All of these exhibit prominent cutaneous abnormalities that involve dermatologists in their diagnosis and management. Most, but not all, are also characterized by an increased risk of malignancies. This demonstrates that the maintenance of genome integrity is of utmost importance for the prevention of malignant transformation. Malignant transformation requires the accumulation of several mutations in specific genes of a single cell. Thus a mutator phenotype is often regarded a prerequisite for carcinogenesis, because without genome instability it would be exceedingly unlikely that all of those mutations occur in a single cell.1–4 The same genes that are affected in the hereditary genome instability disorders can also confer genome instability to individual cells when impaired through acquired mutations, thereby playing an important role early in spontaneous carcinogenesis.

In addition, although these heritable diseases are rare (of the order of 10−5 or 10−6), carriers of the affected genes may comprise several percent of the general population. These individuals are usually free of clinical symptoms, as most of these disorders are characterized by autosomal recessive inheritance. However, epidemiologic studies suggest that heterozygotic carriers may have an increased risk of neoplasia as well.5,6

Spontaneous genome instability is present in Bloom syndrome (BS), ataxia telangiectasia, and Fanconi anemia (FA) as manifested by increased chromosome breakage in primary blood or skin cells. On the other hand, genome instability is present in cells from patients with xeroderma pigmentosum (XP) only after exposure to DNA-damaging agents such as UV radiation or other carcinogens such as benzo[a]pyrene, which is present in cigarette smoke. In XP, many of the severe disease manifestations such as cancer and corneal scarring leading to blindness are the result of the interplay between genetic risk and environmental exposure. For example, XP patients who avoid UV radiation dramatically reduce or eliminate the probability of developing skin cancer and blindness.

In some of the disorders discussed here, genome instability is caused by an impaired ability to repair damage to DNA introduced by certain physical or chemical agents. Cells are equipped with different DNA repair pathways (reviewed in Chapter 110) that repair different types of DNA damage. The nucleotide excision repair (NER) pathway, which processes bulky DNA lesions, including UV-induced DNA photoproducts, is impaired in XP, Cockayne syndrome (CS), and trichothiodystrophy (TTD). Cells from patients with these conditions are characterized by increased killing and mutation formation following exposure to UV radiation. However, only XP patients have increased cancer risk. The reason for this difference in cancer risk is not known.

Proteins encoded by some of the affected genes in these three disorders are not only involved in DNA repair, but also in transcription and cellular DNA damage responses. Thus, mutations affecting different functions of the same gene (such as nervous system development or immune competence) appear to play a role in various phenotypes that are not directly linked to DNA repair functions and underlie several overlap syndromes between those three conditions (Table 139-3). Multiple clinical phenotypes of DNA repair diseases have been recognized. Defects in many genes have been associated with these clinical phenotypes. Mutations in different DNA repair genes can be associated with the same clinical phenotype. On the other hand, different mutations in one DNA repair gene can be associated with different clinical phenotypes. For example, mutations in the XPD(ERCC2) gene have been associated with the following clinical phenotypes: XP, XP with neurologic abnormalities, the XP-Cockayne syndrome complex (XP/CS), XP/TTD, COFS (cerebro-oculofacio-skeletal syndrome), or CS/TTD. XP variant, which is clinically indistinguishable from XP, is a disorder of DNA damage tolerance. Although normal cells can bypass DNA damage during replication (translesional DNA synthesis), cells from XP-variant patients have a defect in this process. The DNA mismatch repair pathway (see Chapter 110) is affected in hereditary nonpolyposis colon cancer (Lynch syndrome) and its subform, Muir–Torre syndrome. Muir-Torre syndrome has cutaneous features including sebaceous gland tumors. These are reviewed in Chapter 153.

Helicases are proteins that unwind DNA and are required for a multitude of metabolic processes involving DNA, such as transcription, replication, repair, and more. Two genes involved in NER are helicases that are also part of the basal transcription factor, TFIIH. The XPB (ERCC3) gene product unwinds DNA in the 3′ to 5′ direction whereas the XPD (ERCC2) gene product unwinds DNA in the opposite direction. The RecQ family of DNA helicases is highly conserved in evolution from bacteria to humans.7,8 Of the five known human RecQ family members, three [(1) BLM, (2) WRN, and (3) RECQL4, which cause BS, Werner syndrome (WS), and Rothmund–Thomson syndrome (RTS), respectively] are mutated in distinct clinical disorders associated with chromosomal instability, cancer predisposition, and/or premature aging.9

Genetic instability can also result from abnormal telomere maintenance. Telomeres are long nucleotide (TTAGGG)n repeats that are important for the maintenance of chromosomal integrity.10 Some telomeric repeats are lost at each cell division and shortened telomere lengths are a feature of aged cells. Accelerated telomere shortening is a hallmark of cells from patients with the cancer-prone disorder dyskeratosis congenita. In about half of dyskeratosis congenita patients, mutations have been found in one out of six genes involved in telomere maintenance.11

BASC (BRCA1-associated genome surveillance complex) is a multienzyme complex centered around the BRCA1 protein in the nucleus.12 It contains important DNA damage response proteins including ATM, ATR, the MRE11-RAD50-NBS1 complex, BRCA1, BLM, FANCD2, and MLH1. These proteins physically interact with each other. Genome instability may result from a defect in any of those and cause the genome instability disorders ataxia-telangiectasia (reviewed in Chapter 143), Seckel syndrome, Nijmegen breakage syndrome, hereditary breast cancer, BS, FA, or hereditary colon cancer. BS and FA are reviewed here.

Xeroderma Pigmentosum

XP serves as the prototype heritable disease with increased sensitivity to cellular injury.12–14 XP is an autosomal recessive disease with sun sensitivity, photophobia, early onset of lentigines and freckling, and subsequent neoplastic changes on sun-exposed surfaces. There is cellular hypersensitivity to UV radiation and to certain chemicals in association with abnormal DNA repair. Some of the patients have progressive neurologic degeneration.

Frequency

XP occurs with a frequency of about 1 in 1 million persons in Europe and the United States15,16 It is relatively more common in areas such as the Middle East where marriage of close relatives is practiced. Patients have been reported worldwide in all races, including whites, Asians, blacks, and Native Americans.

Clinical Features

Skin

Approximately one-half the patients with XP have a history of acute sunburn reaction on minimal UV exposure. The other patients tan normally without excessive burning. In all patients, numerous freckle-like hyperpigmented macules (lentigines) appear predominately on sun-exposed skin (Fig. 139-1). The median age of onset of the cutaneous symptoms in XP is between 1 and 2 years (Fig. 139-2).14 These generally spare sun-protected sites such as the buttocks (see Fig. 139-1D). However, some severely sun-exposed patients may show pigmentary abnormalities in the axillae. Continued sun exposure causes the patient's skin to become dry and parchment-like, with increased pigmentation, hence the name xeroderma pigmentosum (“dry pigmented skin”; see Fig. 139-1A). Premalignant actinic keratoses develop at an early age (see Fig. 139-1B). The appearance of sun-exposed skin in children with XP is similar to that occurring in farmers and sailors after many years of extreme sun exposure.

Cancer

Patients with XP younger than 20 years of age have a greater than 10,000-fold increased risk of cutaneous basal cell carcinoma, squamous cell carcinoma, or melanoma.12,13,16,17 The median age of onset of nonmelanoma skin cancer reported in patients with XP is 8 years. This 50-year reduction in comparison with the general population is an indication of the importance of DNA repair in protection from skin cancer in unaffected individuals (see Fig. 139-2).

Review of the world's literature on XP has revealed a substantial number of cases of oral cavity neoplasms, particularly squamous cell carcinoma of the tip of the tongue, a presumed sun-exposed location. Brain (sarcoma and medulloblastoma), central nervous system (astrocytoma of the spinal cord), lung, uterine, breast, pancreatic, gastric, renal, and testicular tumors and leukemia have been reported in a few patients with XP.11,12,15,16 Overall, these reports suggest an approximate 10- to 20-fold increase in internal neoplasms in XP.

Eyes

Ocular abnormalities are almost as common as the cutaneous abnormalities and are an important feature of XP (see Fig. 139-1C).14,18,19 The posterior portion of the eye (retina) is shielded from UV radiation by the anterior portion (lids, cornea, and conjunctiva). Clinical findings are strikingly limited to these anterior, UV-exposed structures. Photophobia is often present and may be associated with prominent conjunctival injection. Schirmer's testing frequently reveals reduced tearing leading to dry eyes. Continued UV exposure of the eye may result in severe keratitis, leading to corneal opacification and vascularization. The lids develop increased pigmentation and loss of lashes. Atrophy of the skin of the lids results in ectropion, entropion, or, in severe cases, complete loss of the lids. Benign conjunctival inflammatory masses or papillomas of the lids may be present. Epithelioma, squamous cell carcinoma, and melanoma of UV-exposed portions of the eye are common. The ocular manifestations may be more severe in black patients.20

Neurologic System

Neurologic abnormalities have been reported in approximately 30% of the patients.13,21 The onset may be early in infancy or, in some patients, delayed until the second decade. The neurologic abnormalities may be mild (e.g., isolated hyporeflexia) or severe, with progressive mental retardation, sensorineural deafness (beginning with high-frequency hearing loss), spasticity, or seizures. The most severe form, known as the De Sanctis–Cacchione syndrome, involves the cutaneous and ocular manifestations of classic XP plus additional neurologic and somatic abnormalities, including microcephaly, progressive mental deterioration, low intelligence, hyporeflexia or areflexia, choreoathetosis, ataxia, spasticity, Achilles tendon shortening leading to eventual quadriparesis, dwarfism, and immature sexual development. The complete De Sanctis–Cacchione syndrome has been recognized in very few patients; however, many patients with XP have one or more of its neurologic features. In clinical practice, deep tendon reflex testing and routine audiometry usually can serve as a screen for the presence of XP-associated neurologic abnormalities. In cases where there is clinical evidence of early neurologic abnormalities, a brain magnetic resonance imaging (MRI) may show enlarged ventricles.

The predominant neuropathologic abnormality found at autopsy in patients with neurologic symptoms was loss (or absence) of neurons, particularly in the cerebrum and cerebellum. There is evidence for a primary axonal degeneration in these patients.20 In a long term follow-up study of 106 XP patients those with neurodegeneration had a younger age at death (29 years) than those without neurodegeneration (37 years).

Laboratory Abnormalities

Cellular Hypersensitivity

Cultured cells from patients with XP generally grow normally when not exposed to damaging agents. However, the population growth rate or single-cell colony-forming ability is reduced to a greater extent than normal cells after exposure to UV radiation. A range of post-UV colony-forming abilities has been found with fibroblasts from patients, some having extremely low post-UV colony-forming ability and others having nearly normal survival (see Chapter 110).12,14

XP fibroblasts are deficient in their ability to repair some UV-damaged viruses or plasmids to a functionally active state.12,14,20 These host cell reactivation assays have detected an abnormality in every form of XP tested.

UV-irradiated XP fibroblasts are hypermutable compared to normal fibroblasts. This post-UV hypermutability is believed to be the basis of the increased frequency of sunlight-induced somatic mutations that lead to cancer in XP patients.22

Chromosome Abnormalities

XP cells generally are found to have a normal karyotype without excessive chromosome breakage or increased sister chromatid exchanges (as seen in BS). However, after exposure to UV radiation, abnormally large increases in chromosome breakage and in sister chromatid exchanges have been observed.23 The extent of this induced abnormality varies in different patients.

DNA Repair

In 1968, hypersensitivity of cultured XP cells to UV damage was reported by Cleaver24 to be the result of defective DNA repair. He found defective UV-induced repair replication, indicating a defect in the NER pathway. Most XP cells have a normal response to treatment with X-rays, indicating the specificity of the DNA repair defect.25 The defective genes for the seven NER-defective forms of XP and the XP variant have been cloned26 and their functions are being investigated (see Chapter 110).

Complementation Groups

Genetic heterogeneity among the XP DNA repair defects was found by fusing cultured fibroblasts from different patients and defining complementation groups (see Chapter 110). Up to 2011, seven such DNA excision repair-deficient complementation groups have been identified (named XP-A to XP-G) and the corresponding genes have been identified (see Table 139-3).26 Additional patients with clinical XP but normal NER have been called XP variants. Studies of cellular hypersensitivity revealed a slightly increased sensitivity to UV-induced inhibition of cell growth that was potentiated by caffeine. Cells from XP-variant patients have a defect in an error-prone DNA polymerase (pol η) that bypasses unrepaired DNA damage.27,28

Prenatal Diagnosis

Prenatal diagnosis has been reported by measuring UV-induced unscheduled DNA synthesis in cultured amniotic fluid cells29 and by use of DNA diagnosis of trophoblast cells obtained early in pregnancy.30,31 DNA-based prenatal diagnosis may also be possible in selected cases.32

Drug and Chemical Hypersensitivity

A number of DNA-damaging agents other than UV radiation have been found to yield hypersensitive responses with XP cells. These agents include drugs (psoralens, chlorpromazine), cancer chemotherapeutic agents (cisplatin,33 carmustine), and chemical carcinogens (benzo[a]pyrene derivatives). Presumably, these agents induce DNA damage whose repair involves portions of the DNA repair pathways that are defective in XP.33

Treatment

Management of patients with XP is based on early diagnosis, lifelong protection from UV radiation exposure, and early detection and treatment of neoplasms. Diagnosis rests on recognition of the characteristic clinical features and is confirmed by laboratory tests of cellular hypersensitivity to UV and defective DNA repair (see Chapter 110). Molecular determination of some of the XP disease-causing mutations is offered in a laboratory that is certified for clinical testing (see http://genetests.org for the most recent listing).

Sun Protection

Patients should be educated to protect all body surfaces from UV radiation by wearing protective clothing and UV-absorbing glasses and long hair styles. They should adopt a lifestyle to minimize UV exposure and use sunscreens with high sun protective factor (SPF) ratings (minimum SPF 30) daily. Patients should be examined frequently by a family member who has been instructed in recognition of cutaneous neoplasms. A set of color photographs of the entire skin surface with close-ups of lesions (including a ruler) is often extremely useful to both the patient and the physician in detecting new lesions. A physician should examine patients at frequent intervals (approximately every 3–6 months depending on severity of skin disease). Premalignant lesions such as actinic keratoses may be treated by freezing with liquid nitrogen, or with topical 5-fluorouracil or imiquimod. Photodynamic therapy, using, for example, the topical photosensitizer 5-aminolevulinic acid followed by exposure to blue light, is an effective treatment modality for normal patients with multiple actinic keratoses. There are no data on the safety or efficacy of this treatment in XP patients. Caution is recommended because an abnormal response to photodynamic therapy or other light- or laser-based therapies cannot be excluded in XP cells. Larger areas have been treated with therapeutic dermatome shaving or dermabrasion to remove the more damaged superficial epidermal layers.34–37 This procedure permits repopulation by relatively UV-shielded cells from the follicles and glands.38

Because cells from patients with XP are also hypersensitive to environmental mutagens such as benzo[a]pyrene found in cigarette smoke, prudence dictates that patients should be protected against these agents. One of our patients who smoked cigarettes for more than 10 years died of bronchogenic carcinoma of the lungs at age 35 years and another patient who smoked has developed a lung cancer at age 48 years.39 Thus, we recommend that XP patients refrain from smoking cigarettes and that parents should protect children with XP from being exposed to secondhand smoke.

Cancer

Cutaneous neoplasms are treated in the same manner as in patients who do not have XP. This involves electrodesiccation and curettage, surgical excision, or Mohs micrographic surgery (see Chapters 115 and 244). Because multiple surgical procedures are often necessary, removal of undamaged skin should be minimized. Extremely severe cases have been treated by excision of large portions of the facial surface and grafting with uninvolved skin.35

Most patients with XP are not abnormally sensitive to therapeutic X-rays, and XP patients have responded normally to full doses of therapeutic X-radiation for treatment of inoperable neoplasms such as an astrocytoma of the spinal cord,40 a frontal lobe astrocytoma, or recurrent squamous cell carcinoma in the orbit. However, cultured cells from two XP patients were found to be hypersensitive to X-rays,41,42 so when X-ray therapy is indicated, an initial small dose is advisable to test for clinical hypersensitivity.

Oral isotretinoin has been shown in a controlled study to be effective in preventing new neoplasms in patients with multiple skin cancers.43 Because of its toxicity (hepatic, hyperlipidemic, teratogenic, calcification of ligaments and tendons, premature closure of the epiphyses), oral isotretinoin should be reserved for patients with XP who are actively developing large numbers of new skin cancers. We found that the effective dose varies among patients and some patients may respond to doses of oral isotretinoin as low as 0.5 mg/kg/day.

A bacterial DNA repair enzyme, denV T4 endonuclease, in a topical liposome-containing preparation, has been reported to reduce the frequency of new actinic keratoses and basal cell carcinomas in XP patients in one research study.44 As of 2010, this treatment has not been approved by the U.S. Food and Drug Administration.

A study treating multiple melanoma in-situ lesions with intralesional interferon-α in one XP patient showed localized clearing only of lesions injected with the intralesional interferon-α but not with the control diluent.45 There are several case reports of XP patients responding to topical treatment with the immune modulator imiquimod (see Chapter 221).46–49 However, none of these reported long-term follow-up.

Eyes

The eyes should be protected by wearing UV-absorbing glasses with side shields. Methylcellulose eye drops can be used to keep the cornea moist. Corneal transplantation has restored vision in patients with corneal opacity from severe keratitis. However, some of these suffered graft rejection due to neovascularization. Neoplasms of the lids, conjunctiva, and cornea are usually treated surgically.50–52 We are examining the possibility of using a swab to obtain cytologic specimens from the surface of the eye to determine if early neoplasms can be detected or excluded without the need for performing biopsies.

Clinical-Laboratory Correlations

Patients with XP are hypersensitive to UV radiation, as are their cultured cells. Cutaneous and ocular abnormalities are strikingly limited to UV-exposed areas and usually spare such UV-shielded locations as the axillae, buttocks, and retina. The fact that black patients with XP have an increased frequency of skin cancer suggests that a normally functioning DNA repair system provides greater protection against skin cancer than does the natural pigmentation of black skin.

Complementation Groups

At least eight different molecular defects are associated with the clinical abnormalities recognized as XP, as indicated by the existence of seven DNA excision repair-deficient complementation groups (A to G) and the variant form. A discussion of the cloned XP genes and their function can be found in Chapter 110. A Web site listing disease-causing mutations in XP and CS genes has been established at http://xpmutations.org/. There is a complex relationship among the DNA repair genes and clinical disease (see Table 139-3 and see http://genetests.org for review of xeroderma pigmentosum). Multiple NER genes are associated with at least a spectrum of different clinical phenotypes. A clinical phenotype can be associated with defects in each of several genes. Conversely, mutations in one gene can be associated with several different clinical phenotypes. These complex relationships and the roles of DNA repair genes in regulation of transcription and in immune functions are under intense investigation.

Complementation Group a

Complementation group A (see Table 139-3) contains patients with the most severe neurologic and somatic abnormalities (the De Sanctis–Cacchione syndrome) as well as patients with minimal or no neurologic abnormalities.13 Long-term follow-up of these patients has revealed a relationship between the genotype and the phenotype. Patients with the most severe disease appear to have truncating mutations in both alleles of the XPA gene leading to no detectible normal protein. In contrast, patients with minimal neurologic abnormalities have splice-site mutations that permit a small amount of normal messenger RNA (mRNA) to be made. This form is seen in the United States, Europe, and the Middle East. It is the most common form of XP in Japan. Approximately 90% of Japanese XP-A patients have the same single-base-substitution founder mutation.53 This finding has served as the basis for development of a rapid diagnostic assay for Japanese XP-A patients (including prenatal diagnosis) using polymerase chain reaction analysis of a small sample of DNA.37 Heterozygous carriers of this disease-causing mutation who have one mutated allele and one normal allele have been estimated to comprise approximately 1% of the Japanese population.16

Complementation Group B

Complementation group B (Fig. 139-3) is composed of five patients in four kindreds who had the cutaneous abnormalities characteristic of XP (including neoplasms) in conjunction with neurologic and ocular abnormalities typical of CS.13,54 Another family had two adult sisters with XP without CS who had ocular melanomas and were parents of normal children. Surprisingly, a patient with TTD also was found to have a defect in the XPB gene.

Complementation Group C

Patients in complementation group C, with rare exceptions, have XP with skin and ocular involvement but without neurologic abnormalities.13,55–61 This is the most common group in the United States, Europe, and Egypt, but has been found rarely in Japan. Most patients have truncating mutations in both alleles leading to undetectable levels of XPC mRNA (due to nonsense-mediated message decay). However, a splice lariat branchpoint mutation resulting in as little as 3% to 5% of normal mRNA resulted in milder clinical symptoms in one family in Turkey.58 XP-C patients typically do not give a history of severe blistering sunburns on minimal sun exposure and at times are first diagnosed with the appearance of skin cancer in a child. One XP-C patient was reported to be hypersensitive to ionizing radiation42; however, correction of the XPC gene defect did not correct the cellular ionizing radiation hypersensitivity, suggesting that more than one gene was defective in this patient.

Complementation Group D

Patients in complementation group D have been described with several different clinical phenotypes. They may have cutaneous XP with late onset of neurologic abnormalities in their second decade of life or XP with no neurologic abnormalities.13,62 Two XP-D patients have been reported with clinical symptoms of both XP and CS. Cells from patients with a photosensitive form of TTD (without XP) also were assigned to the XP complementation group D. Two patients were reported with combined symptoms of both TTD and XP (one patient had a skin cancer and another died of metastatic melanoma) and mutations in the XPD gene.63 Finally, a patient with cerebro-oculo-facio-skeletal (COFS) syndrome had a mutation in the XPD gene.64

Complementation Group E

Complementation group E was found in one kindred in Europe and several in Japan.13,65 We have studied adult patients with multiple skin cancer in 3 kindreds in the US and Germany. These patients had no neurologic involvement.66

Complementation Group F

Complementation group F patients have been found mainly in Japan.67,68 Most of these patients have mild clinical symptoms without neurologic abnormalities or skin cancer. However, we recently found two families with adult onset of severe neurodegeneration with mutations in the XPF gene. The residual rate of DNA repair is very low (only 10% to 20% of normal).

Complementation Group G

Thirteen patients in XP complementation group G have been identified in the United States, Europe, and Japan (Fig. 139-4).69 There is a large variation in clinical features among these patients. Several patients with mutations in the XPG gene had clinical features of both XP and severe CS with cachexia and death in the first decade (see Fig. 139-3). Other patients with different mutations in the same gene had no neurologic abnormalities.

Xeroderma Pigmentosum Variant

XP-variant cells have normal DNA NER and thus do not fall into any of the complementation groups of cells with defective DNA excision repair.14 However, there is a defect in an error-prone, translesional DNA damage bypass polymerase, pol η (see Chapter 110).25,27,70 Most XP-variant patients have clinical XP with no neurologic abnormalities.71 The cutaneous and ocular abnormalities have been severe in some patients and mild in others.

Heterozygotes

XP heterozygotes (parents and some other relatives) are carriers of the gene for XP but are clinically normal. There is limited epidemiologic evidence to indicate that such persons have an increased risk of developing skin cancer.72 Most tests of cell function or DNA repair yield normal responses with cells from XP heterozygotes.

Patient Support Groups

The Xeroderma Pigmentosum Society is an educational, advocacy, and support organization for XP patients and their families: Xeroderma Pigmentosum Society, Inc., Box 4759, Poughkeepsie, NY 12602–4759; Web site: http://www.xps.org; e-mail: xps@xps.org; telephone: toll-free (877) XPS-CURE (877-977-2873). Another support group is the XP Family Support Group, 8375 Folsom Blvd Suite 201, Sacramento Ca, 95826. Their Web site is http://www.xpfamilysupport.org/. A Web site listing disease-causing mutations in XP and CS genes has been established at http://xpmutations.org/.

Cockayne Syndrome (Including Xeroderma Pigmentosum–Cockayne Syndrome Overlap)

CS is a very rare, autosomal recessive degenerative disease with cutaneous, ocular, neurologic, and somatic abnormalities (see Table 139-1).73,74 A review published in 1992 described 140 cases reported in the literature.75

Clinical Features

In 1936, E. A. Cockayne described a syndrome characterized by cachectic dwarfism, deafness, and pigmentary retinal degeneration with a characteristic “salt and pepper” appearance of the retina.76 The skin had photosensitivity without the excessive pigmentary abnormalities seen in XP. There was marked loss of subcutaneous fat, resulting in a “wizened” appearance with typical “bird-headed” facies and prominent “Mickey Mouse” ears. Other ocular findings included cataracts and optic atrophy.77 Neurologic abnormalities, in addition to deafness, include peripheral neuropathy, normal pressure hydrocephalus, and microcephaly. Birth weight and early development are usually normal. The disease onset is usually in the second year of life with slowly progressive neurologic degeneration. Intellectual deterioration may be nonuniform, with some functions preserved better than others. A severe infantile form has been described78,79 as well as a milder form with late onset. COFS syndrome64,80,81 with microcephaly and severe mental retardation and CAMFAK syndrome of congenital cataracts, microcephaly, failure to thrive, and kyphoscoliosis82 have some similar features. CS is not associated with an increased incidence of neoplasia.

Laboratory Abnormalities

Clinical laboratory testing often shows sensorineural deafness, neuropathic electromyogram, and slow motor nerve conduction velocity.13,20,69,75,78,83 The electroencephalogram may be abnormal, and X-ray examination may show thickened skull and microcephaly. Computed tomography may be diagnostically useful in the detection of normal-pressure hydrocephalus and showing calcification of the basal ganglia and other structures (see eFig. 139-4.1). MRI of the brain shows atrophy and dysmyelination of the cerebrum and cerebellum. Bone age is usually normal. Height and weight are usually well below the third percentile for the age.

Cellular Hypersensitivity

As with XP, cultured cells (fibroblasts or lymphocytes) from patients with CS are hypersensitive to UV-induced inhibition of growth and colony-forming ability.13,84 Host cell reactivation of UV-damaged adenovirus or plasmids is reduced, although generally to a lesser extent than in XP. There are two complementation groups (A and B) in CS (see Table 139-3). Patients with defects in CSA or CSB have similar features.75 A recent report from Europe identified CSA (ERCC8) and CSB (ERCC6) mutations in 84 kindreds. 62% (52) had mutations in the CSB gene.85 A patient with COFS syndrome was reported with a defect in CSB82 and another with a defect in XPD (Table 139-3).57 Molecular determination of some of the CS disease-causing mutations is offered in a laboratory that is certified for clinical testing (see http://genetests.org for the most recent listing).

Prenatal Diagnosis

Prenatal diagnosis of CS has been performed86 based on the delay in recovery of post-UV RNA synthesis and the increased cell killing by UV radiation.

Clinical-Laboratory Correlation

Patients with defects in CSA or CSB have similar clinical features.75

Patient Support Group

The Share and Care Cockayne syndrome network (http://cockaynesyndrome.net or http://www.cockayne-syndrome.org) is an educational, advocacy, and support organization for CS patients and their families (Box 570618, Dallas, TX 75357).

Xeroderma Pigmentosum–Cockayne Syndrome Complex

Approximately one dozen patients with CS have been found to have, in addition, clinical features of XP.19,48,61 These features include freckle-like pigmentation on sun-exposed skin and cutaneous neoplasms (see Fig. 139-4). Cells from these XP/CS patients have reduced DNA excision repair characteristic of XP. Clinically, these patients may be distinguished from XP patients with neurologic abnormalities by the presence of the CS features of pigmentary retinal degeneration, calcification of the basal ganglia, normal-pressure hydrocephalus, and hyperreflexia. Cells from patients with this complex have been found to have mutations in three different XP genes: XPB, XPD, and XPG,54,59,84 demonstrating that several different genes are implicated in this disorder (see Table 139-3).

Trichothiodystrophy

TTD is a rare autosomal recessive disorder that is characterized by sulfur deficient, brittle hair and includes a broad spectrum of clinical abnormalities that may include photosensitivity, ichthyosis, intellectual impairment, short stature, microcephaly, characteristic facial features (protruding ears, micrognathia), recurrent infections, bilateral cataracts, dystrophic nails, and other features (Fig. 139-5).85–94 Bone abnormalities include osteosclerosis of the axial skeleton with osteopenia of the limbs. Decreased red blood cell mean corpuscular volume and increased hemoglobin A2 levels mimic β-thalassemia trait. eTable 139-3.1 lists the clinical findings in one TTD patient, as an example of the diverse findings.85 Developmental delay may be associated with dysmyelination,96 a feature similar to CS; however, patients do not have retinal changes of CS. The spectrum of clinical involvement is broad ranging from only hair to severe multisystem abnormalities (Fig. 139-5). TTD encompasses patients who have been described as Tay syndrome, Amish brittle hair syndrome, Sabinas brittle hair syndrome, or Pollitt syndrome.

In 1980, Price proposed the term trichothiodystrophy [derived from Greek tricho: hair; thio: sulfur; dys: faulty; trophe: nourishment] recognizing the hair shaft sulfur deficiency as a marker for this symptom complex.90 While most TTD patients have short, broken hair (Figs. 139-5A, 139-5C, and 139-5D), some patients have long hair (Fig. 139-5B). Under light microscopy with polarization, TTD hair shafts have a characteristic dark and light banding pattern that gives a “tiger tail” appearance (Fig. 139-5E). In addition, they usually have hair shaft abnormalities including trichoschisis (a clean transverse break through the hair) (Fig. 139-5G), trichorrhexis nodosa-like defects, and ribboning (Fig. 139-5H).79,80 Hair shafts are brittle because of a reduction of high-sulfur matrix proteins, and amino acid analysis of the hair demonstrates reduced levels of cysteine and cystine in hair shaft proteins.97 This is associated with a decrease in the ratio of strong to weak disulfide bonds within the hair shafts.91 Approximately 50% of TTD patients have clinical photosensitivity that ranges from subtle to severe. However, in contrast to the typical clinical features of XP, patients with TTD do not develop poikilodermatous changes (hyper- and hypopigmentation, telangiectasias, and atrophy) or skin cancer. Rarely, patients may have an overlap syndrome with features of both TTD and XP, with typical hair features of TTD and the pigmentary and skin cancer characteristic of XP (see Table 139-3).63

The majority of TTD patients have a defect in XPD (ERCC2). A few have mutations in XPB (ERCC3) or TTDA (TFB5) genes, which are components of the transcription factor TFIIH that regulates both DNA repair and transcription. Some TTD patients have mutations in TTDN1, a gene of unknown function.98 It is believed that mutations that affect the repair function of the NER genes are associated with features of XP, whereas mutations affecting the transcription-related function results in features of TTD.99

The diagnosis of TTD is based on examination of hair shafts (Fig. 139-5E–H). TTD hair shafts display tiger tail banding under polarizing microscopy. In addition, they show a spectrum of typical hair shaft abnormalities, including trichoschisis, trichorrhexis nodosa-like fractures, surface irregularities, and ribboning.88,89 Amino acid analysis of hair shafts can confirm reduced levels of cysteine and cystine (see Chapter 88).

A recent review of the literature identified 112 patients, whose clinical features are detailed in eTable 139-3.2. Patients with TTD show a wide spectrum of clinical findings, including abnormal characteristics at birth, pregnancy complications in mothers carrying an affected fetus, ocular abnormalities and infections (eTable 139-3.1).100,101 Clinical features of photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature have been used to describe patients with the acronyms PIBIDS, IBIDS, and BIDS. While patients can be found who fit having these features, all of these individuals have additional clinical findings, making these acronyms poor descriptors of the actual disease features. Moreover, more than a third of patients do not fit these acronyms. Because they are misleading they should be abandoned.

Management includes sun protection and varies with the individual clinical features. Patients with developmental delay and intellectual impairment may have dysmyelination as seen on MRI of the brain and may benefit from neurologic and developmental assessment and rehabilitation medicine consultation. Ophthalmologic involvement can include cataracts (which may be congenital), nystagmus, and errors of refraction.102 A review of the literature identified a high mortality (>20%) in children below the age of 10, with most deaths due to infection. In some patients, recurrent infections have been managed with prophylactic antibiotics or intravenous immunoglobulin. Patients with skeletal abnormalities may benefit from rehabilitation medicine evaluation and support. In addition, a high frequency of complications occur during pregnancies, including intrauterine growth restriction, preeclampsia, preterm delivery, hemolysis-elevated liver enzymes-low platelets (HELLP) syndrome, and abnormal levels of maternal serum screening markers, highlighting the role of DNA repair in normal development.103 Several our TTD patients in their first or second decade of life have experienced progressive inability to walk over a few year interval resulting from bilateral aseptic necrosis of their hips.

Bloom Syndrome

BS is a rare, autosomal recessive disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency, and predisposition to a variety of different cancers.7,104 It is most frequent among Ashkenazi Jews.105 Approximately 250 patients have been recognized.

Clinical Features

Facial erythema and telangiectasia superficially resembling lupus erythematosus (Fig. 139-6) are often present within the first few weeks after birth in the malar area, on the nose, and around the ears.104 Sun exposure accentuates these abnormalities and may induce bullae, bleeding, and crusting of the lips and eyelids. Café-au-lait spots are common, at times accompanied by adjacent depigmented areas. Patients are well proportioned but small. Adult height is usually under 150 cm. Patients have a long, narrow head with a characteristic facies consisting of a narrow, prominent nose, relatively hypoplastic malar areas, and a receding chin.

Patients with BS are predisposed to multiple infections, as there is immune dysfunction. Fertility is decreased and diabetes mellitus is common. Approximately 20% of patients with BS develop malignancies, comprising a normal spectrum of cancer types, of which one-half occur before age 20 years.104 Patients usually die before the age of 30 years from either cancer or infection.

Gene Defect, Pathogenesis, and Laboratory Abnormalities

BS is caused by mutations in BLM, which encodes a RecQ helicase.7,9,105,106,107 BS cells are characterized by an increase in the frequency of spontaneous sister chromatid exchanges (see Chapter 110) and in exchanges between homologous chromosomes. The latter is often visualized by quadriradial chromosomes. These are four-armed chromosomes most likely formed by recombination between two chromosomes (and almost never found in unaffected individuals). These observations demonstrate that BS cells are characterized by hyperrecombination. Although the exact mechanisms of how mutations in the BLM helicase lead to hyperrecombination are still not completely understood, it has been suggested that they are related to defective DNA replication or defective resolution of stalled replication forks. Hyperrecombination may result in an increased frequency of loss of heterozygosity and through that mechanism, in conjunction with increased spontaneous mutation frequency, an increased frequency of malignant transformation. The immune deficiency, characterized by diminished immunoglobulin levels, reduced cellular proliferative response to mitogens, and decreased proliferation in the mixed leukocyte reaction, probably further contributes to the increased cancer risk.

Testing

The observation of quadriradial chromosomes (observed in 0.5% to 14% of lymphocytes of BS patients) and the approximately tenfold increased frequency of spontaneous sister chromatid exchanges are used to diagnose BS.108 A founder deletion/insertion mutation in the BLM gene was identified in Ashkenazi Jews at a frequency of approximately 1% (BLMAsh)105,109 and can be used for DNA diagnosis of BS patients and carriers among Ashkenazi Jews.57 Diagnostic testing for BS is offered in a number of laboratories that are certified for clinical testing (see http://genetests.org for the most recent listing).

Werner Syndrome (Adult Progeria)

WS is a rare, autosomal recessive disorder, characterized by several features of premature aging and an increased cancer risk. More than 800 patients have been reported.110 Most of the WS patients are Japanese.

Clinical Features

Patients with WS are clinically normal until adolescence, when they do not show the usual growth spurt and start to prematurely develop features and diseases of aging, including graying and thinning of hair, loss of subcutaneous fat, wrinkling of skin, type 2 diabetes, osteoporosis, and cardiovascular disease secondary to atherosclerosis.111 Often, ophthalmologists are first to make the diagnosis of WS as cataracts develop early.112 Other features that are not part of the normal aging process are scleroderma-like changes with subcutaneous atrophy, leg ulcers, soft tissue calcifications, and bird-like facies. Although an increased incidence and early onset of cancer is related to aging, the 10:1 ratio between epithelial to mesenchymal cancer seen in a normal aging population is shifted to 1:1 in WS patients, with, for example, sarcomas and melanomas being more frequent.113 As in the Japanese general population, most of the melanomas are of the acral-lentiginous type or arise from mucous membranes and are therefore not considered to be related to UV-exposure. Thyroid cancer occurs at a younger age in WS patients than in the Japanese general population. Death usually occurs before the age of 50 years due to either myocardial infarction or cancer.

Gene Defect, Pathogenesis, and Laboratory Abnormalities

WS is caused by a mutation in WRN, which encodes a RecQ helicase.7,114,115 Most mutations of WRN result in truncation of the protein, sometimes by only a small amount, with loss of the nuclear targeting sequence. WRN is involved in many metabolic processes of DNA metabolism and WRN mutations cause various defects in DNA replication, recombination, base excision repair of oxidative DNA damage, repair of DNA strand breaks, DNA damage signaling, and transcription. Cells from WS patients have a reduced replicative lifespan in culture116 and show altered telomere structure and length. Genome instability in WS cells is shown by an increased frequency of nonhomologous chromosome exchanges and of large chromosomal deletions.

Rothmund–Thomson Syndrome

Clinical Features

The hallmark of RTS, a rare, autosomal recessive disorder, is poikiloderma with variegated cutaneous pigmentation, atrophy, and telangiectasias beginning in infancy.117,118 RTS patients are photosensitive and develop prominent erythema and facial swelling on sun exposure early in life, which may be accompanied by blister formation. They often have sparse scalp hair, eyebrows, and eyelashes. Other clinical features include juvenile cataracts, stunted growth, skeletal abnormalities including radial bone defects, and a predisposition for cancer, in particular for osteosarcomas (32% of patients). Five percent of RTS patients also develop nonmelanoma skin cancer.

Gene Defect, Pathogenesis, and Laboratory Abnormalities

Mutations in the helicase RecQL4 have been identified in a majority of patients with RTS.119 Cells from RTS patients are characterized by chromosomal instability with trisomy, aneuploidy, and chromosomal rearrangements, suggesting a role of RECQL4 in maintaining chromosome stability.120,121 RTS cells have also been reported with an increased sensitivity to ionizing radiation with increased formation of chromosome gaps and breaks.120,121 However, this was not confirmed in other patients, possibly reflecting heterogeneity in this disease.122 The exact function of the RECQL4 helicase remains unclear.115,123 Cells from one patient had reduced DNA repair after exposure to UVC.124 One RTS patient had increased acute toxicity after high-dose radiotherapy after surgery and subsequent palliative chemotherapy. However, another RTS patient was reported to have a normal acute response to radiation therapy for a squamous cell carcinoma of his tongue.125 He died 2 years later with extensive squamous cell carcinoma in the thorax, but no tumor in the oral cavity.

Fanconi Anemia

FA is an autosomal recessive disease characterized by progressive pancytopenia, growth retardation, various congenital abnormalities of the heart, kidney, and limbs, and a predisposition to cancer.126,127 More than 1,200 patients have been reported to the International Fanconi Anemia Registry.

Clinical Features

Cutaneous abnormalities are present in almost 80% of patients (Figs. 139-7A–139-7D).126,128,129 Hyperpigmentation is present from birth or early childhood and is diffuse and accentuated over the neck, joints, and trunk. Café-au-lait spots and achromic lesions are also present.

Hematopoietic manifestations usually have their onset before age 10 years and most commonly lead pediatricians to make the diagnosis of FA. These consist of a hypocellular bone marrow with progressive decrease in the number of circulating platelets, granulocytes, and erythrocytes. Skeletal malformations are common and often include aplasia or hypoplasia of the thumb, metacarpals, or radius.130,131 Short stature, renal deformities, strabismus, microphthalmia, hypogonadism, and central nervous system abnormalities, including hyperreflexia and mild mental retardation, are also observed. The frequency of acute myelogenous leukemia has been reported to be elevated 500-fold.132–135 If patients survive aplastic anemia and/or leukemia (e.g., as a result of bone marrow transplantation), they often develop solid tumors by the fifth decade of life, mostly squamous cell carcinomas of the head and neck and the anogenital area.

Gene Defect, Pathogenesis, and Laboratory Abnormalities

FA is genetically heterogeneous with 13 complementation groups (FANCA to FANCN). All 13 genes have been identified and all of the FA proteins have been shown to act in a common DNA damage response signaling pathway, which also involves BRCA1 and BRCA2 (these genes are mutated in hereditary breast cancer; see Chapter 110) and multiple other proteins involved in cellular DNA damage responses.136–147 Activation of this FA/BRCA pathway is thought to mediate DNA recombination to repair DNA strand breaks and DNA cross-links, generated, for example, by ionizing radiation or DNA cross-linking agents and to facilitate resolution of stalled replication forks.

Testing

Increased chromosome breakage after exposure to DNA cross-linking agents such as mitomycin C or diepoxybutane is a feature of FA. Central to the FA/BRCA pathway is the monoubiquitination of the FANCD2 protein. The inability of FA cells to ubiquitinate the FANCD2 protein, as shown in Western blots after, for example, exposure to DNA cross-linking agents, is currently used as a screening tool to confirm the diagnosis of FA. Diagnostic testing for FA is offered in a number of laboratories that are certified for clinical testing (see http://genetests.org for the most recent listing).

Resources: The Fanconi Anemia Research Fund

Patients, physicians, and researchers may obtain information from the Fanconi Anemia Research Fund, Inc. (http://www.fanconi.org) or from Fanconi Canada (http://www.fanconicanada.org).

Dyskeratosis Congenita

Dyskeratosis congenita, the Zinsser–Cole–Engman syndrome, is an X-linked multisystem disease with cutaneous, mucosal, ocular, gastrointestinal, and hematologic abnormalities and an increased incidence of cancer (see Table 139-1). There are also autosomal dominant and autosomal recessive forms. A Registry at Hammersmith Hospital in London recruited 228 families having 354 affected patients from 40 countries.148 More than 500 patients have been reported in the literature.149 Affected females may have either the autosomal dominant or autosomal recessive form.

Clinical Features

The most common features are a triad of reticulated hyperpigmentation, dystrophic nails, and mucosal leukoplakia (see Figs. 139-7E–139-7H).150–152 During the first decade of life, patients develop reticulated poikiloderma of sun-exposed areas, with hyperpigmentation and, occasionally, bullae. Nail dystrophy is present in virtually all patients beginning at approximately age 2–5 years. The nails initially split easily, then develop longitudinal ridging with irregular free edges. Eventually, the nails become smaller, resulting in rudiments remaining. The fingernails are usually involved before the toenails. Other skin abnormalities include atrophic, wrinkled skin over the dorsum of hands and feet and hyperhidrosis and hyperkeratosis of palms and soles with disappearance of dermal ridges (absence of fingerprints).

Leukoplakia may be present in any mucosal site. The oral mucosa is the most frequent, but leukoplakia is also found in the urethra, glans penis, vagina, and rectum. Lingual hyperkeratosis may be present. Mucosal surfaces such as the esophagus, urethra, and lacrimal duct may become constricted and stenotic, resulting in dysphagia, dysuria, and epiphora. Multiple dental caries and early loss of teeth are common. Progressive pulmonary disease, including infections and fibrosis (and cirrhosis in some patients) was reported in 19% of affected males.151 Approximately 20% of the patients had learning difficulties or mental retardation.151 There have been several reports of intracranial calcifications, especially of the basal ganglia.153,154 These are also seen in CS.

There is an increased incidence of neoplasia, particularly squamous cell carcinoma of the mouth, rectum, cervix, vagina, esophagus, and skin. A large British kindred had Hodgkin disease and adenocarcinoma of the pancreas.155 Similar to FA, although hypoplasia is the main abnormality seen in bone marrow, there is a predisposition to both myelodysplasia and acute myeloid leukemia.151

The majority (93%) of patients developed bone marrow failure which was the main cause (71%) of early death.151 Approximately one-half of the patients (21 of 41) developed pancytopenia under the age of 10 years with a hematologic picture similar to FA. Patients have been treated with bone marrow transplantation.156

Laboratory Studies

A gene for dyskeratosis congenita (DKC1) has been cloned,148,157,158 which is located on the q28 region of the X chromosome. The protein, dyskerin, has a nucleolar function, and a role in telomere maintenance and aging.159–163 Mutations in the DKC1 gene have been detected in affected patients.148,164–166 There is also evidence for an autosomal form with affected females148,151,167,168 having mutations in the TERC gene, which is also involved in telomere function. Approximately half of the DC patients have a mutation in a gene in the telomere biology pathway: DKC1, TERC, TERT, TINF2, NOLA2, and NOLA3. Many DC patients have very short telomeres.

Testing

Diagnostic testing for DC is offered in a number of laboratories that are certified for clinical testing (see http://genetests.org for the most recent listing).