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.
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.
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.
Xeroderma pigmentosum. A. Pigmentary changes, atrophy, dryness, and cheilitis in a 16-year-old patient. B. Cheek of a 14-year-old patient with pigmented macules of varying size and intensity, actinic keratosis, basal cell carcinoma, and a surgical scar. C. Corneal clouding, prominent conjunctival blood vasculature, and loss of lashes. D. Myriads of pigmented macules of varying size and intensity and scattered achromic areas on the back, with marked sparing of sun-protected buttocks of a 14-year-old patient.
Xeroderma pigmentosum. Age at onset of clinical symptoms and skin cancer. Age at onset of cutaneous symptoms (generally sun sensitivity or pigmentation) was reported for 430 patients. Age at first skin cancer was reported for 186 patients and is compared with the age distribution for 29,757 patients with basal cell carcinoma or squamous cell carcinoma in the US general population. There is a 50-year reduction in age of onset of skin cancer in the XP patients compared with the US general population. (From Kraemer KH, Lee MM, Scotto J: Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 123:241, 1987, with permission.)
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.
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 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).
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
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.
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).
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 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
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).
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.
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.
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.
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.
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 (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 (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.
Xeroderma pigmentosum (XP/CS) complex. A. 28-year-old patient (XP11BE) in XP complementation group B with cutaneous changes of XP, including pigmentary changes and atrophy. She has a beak-like nose and loss of subcutaneous tissue typical of Cockayne syndrome. B. The patient is of short stature (less than 4 ft. tall). Her mother, an obligate heterozygote, is clinically normal.
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.
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 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 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).
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.
Severe and mild xeroderma pigmentosum XP-G patients. A and B. XP82DC. C–F. XP65BE. A. Patient XP82DC at 3 years of age has deep-set eyes characteristic of Cockayne syndrome (CS) and irregular lentiginous pigmentation on her face characteristic of XP, indicating XP/CS complex. B. Patient XP82DC at 3 years of age has characteristic XP-pigmented lesions on her forearms and dorsa of hands along with thin, translucent skin with readily visible veins. The small size of her hands is apparent in comparison with the hands of her mother. C. Patient XP65BE at age 6 months experienced severe sunburn on her face with minimal sun exposure. Erythema and swelling are seen on skin of forehead, cheeks, and periorbital area. D. Patient XP65BE at age 9 months shows erythema and peeling of skin of malar area of face after sun exposure. E. Patient XP65BE at age 4.5 years shows pigmentary changes on her nose, malar area, and other portions of her face. F. Patient XP65BE at 4.5 years shows blistering sunburn on her upper thigh. Note spared area above knee where sunscreen was applied G. Patient XP65BE shows minimal pigmentary changes on face and sparing of neck and hand. She used measures to protect her skin from sun exposure. (From Emmert S et al: Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients. J Invest Dermatol 118:972, 2002, with permission.)
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.
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.
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: email@example.com; 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
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.
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.
Cockayne syndrome. Calcification of brain visualized on computed tomography scan. A. A 2-year-old patient with bilateral calcification of basal ganglia (arrow). B. A 15-year-old patient with extensive calcification involving basal ganglia, cerebellum, and cerebral hemispheres (arrows).
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 of CS has been performed86 based on the delay in recovery of post-UV RNA synthesis and the increased cell killing by UV radiation.
Patients with defects in CSA or CSB have similar clinical features.75
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).
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.
Trichothiodystrophy (TTD): clinical and microscopic hair findings. A. Three-year-old girl with TTD having short brittle hair that is sparse and broken off at different lengths. She rarely has haircuts except to trim uneven hairs. She has developmental delay. B. Seven-year-old boy with TTD with sun sensitivity, congenital cataracts, multiple infections, and developmental delay. In contrast to the patient in A, he has long hair. He has a happy engaging personality. C and D. Severe clinical phenotype: 14-year-old boy with short brittle hair and dysmorphic facies with protruding ears, micrognathia, deep set eyes, head elongation in fronto-occipital plane. He also has ichthyosis, intellectual impairment, short stature, photosensitivity, osteosclerosis, neurologic abnormalities, and recurrent infections. Light microscopy findings: E. TTD hairs displaying alternating light and dark “tiger tail” bands using polarizing microscopy. F. Irregular, undulating hair shaft with light microscopy G. Trichoschisis (arrow): clean, transverse cleavage fracture; marked narrowing of shaft diameter (asterisk). H. Ribboning. (Modified from Liang C et al: Characterization of tiger tail banding and hair shaft abnormalities in trichothiodystrophy. J Am Acad Dermatol 52:224, 2005.)
eTable 139-3.1 Clinical Features of a Patient with Trichothiodystrophy (TTD421BEa), Showing the Broad Array of Abnormalities ||Download (.pdf)
eTable 139-3.1 Clinical Features of a Patient with Trichothiodystrophy (TTD421BEa), Showing the Broad Array of Abnormalities
- Hair abnormalities: Tiger-tail banding; brittle hair; sparse hair; other hair shaft abnormalities
- Nail abnormalities: Brittle nails; koilonychia; soft nails
- Skin abnormalities: Ichthyosis; photosensitivity; hypohidrosis
- Oral abnormalities: High-arched palate; abnormal teeth; frequent caries
- Growth abnormalities: Short stature and poor weight gain (3rd percentile) and microcephaly (10th percentile)
- Neonatal skin abnormalities: Collodion membrane; erythroderma
- Neurologic abnormalities: Developmental delay; intellectual impairment; abnormal gait/ataxia; abnormal magnetic resonance imaging (MRI) results (diffuse dysmyelination)
- Personality characteristics: Sociable/engaging/cheerful
- Hematologic/immunologic abnormalities: Recurrent infections (particularly respiratory); neutropenia; elevated hemoglobin A2; low serum IgM
- Maternal pregnancy and fetal abnormalities: Pregnancy-induced hypertension; spotting during pregnancy; abnormal prenatal screening (elevated maternal α-fetoprotein); premature birth; intrauterine growth restriction; birth weight low for gestational age; placental abnormalities
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.
eTable 139-3.2 Clinical Manifestations of 112 Patients with Trichothiodystrophy. Numbers Represent Percentages in Each Groupa ||Download (.pdf)
eTable 139-3.2 Clinical Manifestations of 112 Patients with Trichothiodystrophy. Numbers Represent Percentages in Each Groupa
Total percentage in each group
B (brittle hair/hair shaft abnormality)
I (intellectual impairment/developmental delay)
D (decreased fertility/gonadal dysgenesis)b
S (short stature)
Abnormalities present at birth
DNA repair abnormalityc
- Cell UV sensitivity, unclassified
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.