Shinichi Moriwaki

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

Background The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study. Methods All 106 XP patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up. Results In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10 000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)—a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02). Conclusion This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.

Analysis of photosensitivity in Japanese cancer-bearing patients receiving photodynamic therapy with porfimer sodium (PhotofrinTM)

A major disadvantage of a new cancer treatment, porfimer sodium (PhotofrinTM)‐mediated photodynamic therapy (PF‐PDT), is photosensitivity for several weeks after cessation of the treatment. To characterize persistent sensitivity to visible light following PF‐PDT, phototestings were performed in 59 Japanese cancer‐bearing patients with a slide projector lamp 3 weeks or more after the treatment. The duration of photosensitivity was analyzed in relation to the patients’ sex, skin phototype (SPT), site of tumor and liver function. There was no correlation of the photosensitivity persistency with the site of cancers and the function of liver. However, female subjects needed significantly longer recovery periods than male subjects from potential photosensitivity after PF‐PDT. Patients with SPT2 were significantly more sensitive than patients with SPT3 and 4. These results suggest that the prolonged photosensitivity occurs after PF‐PDT especially in female patients and in cases with a lighter SPT. Such patients should be carefully followed up for post‐PDT photosensitivity.

Amyloidosis cutis dyschromica : DNA repair reduction in the cellular response to UV light

BACKGROUND Amyloidosis cutis dyschromica, a special type of primary cutaneous amyloidosis, is assumed to be a congenital disorder and sun exposure is thought to be the major causal factor. Herein we report a case of this rare disease and DNA repair characteristics of UV damages in the fibroblasts derived from the patient. OBSERVATIONS A 24-year-old Japanese woman showed hyperpigmented and hypopigmented xerotic lesions in sun-exposed skin since she was 10 years old; deposits of amyloid material were detected in the papillary dermis. The fibroblasts were hypersensitive to UV-B, but not so sensitive to UV-C. Unscheduled DNA synthesis of the patients cells after UV-C exposure was lower than that of normal cells at 3 hours and both reached the same level at 6 hours. After UV-B exposure, unscheduled DNA synthesis of the patients cells was lower than that of normal cells at least until 6 hours after UV exposure. CONCLUSION Although the origin of amyloidosis cutis dyschromica is unknown, hypersensitivity to UV-B with possible DNA repair defects is suggested to be the cause of this disease.

Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage.

OBJECTIVE Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. DESIGN Retrospective observational case series. PARTICIPANTS Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. METHODS Complete age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. RESULTS Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. CONCLUSIONS Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage.

Xeroderma pigmentosum complementation group G patient with a novel homozygous missense mutation and no neurological abnormalities

Abstract:  We describe an unusual xeroderma pigmentosum (XP) patient with a mutation in XP complementation group G, representing only the third reported Japanese XP‐G patient. A 40‐year‐old men (XP3HM), born from consanguineous parents experienced sun sensitivity and pigmentary changes of sun‐exposed skin since childhood. He developed a squamous cell carcinoma on his lower lip at the age of 40. He has neither neurological abnormalities nor Cockayne syndrome. The primary fibroblasts of the patient were hypersensitive to killing by UV (D0 = 0.6 J/m2) and the post‐UV unscheduled DNA synthesis was 8% of normal. Host cell reactivation complementation analysis implicated XP complementation group G. We identified a novel homozygous mutation (c.194T>C) in a conserved portion of the XPG(ERCC5) gene, resulting in a predicted amino acid change; p.L65P. We confirmed that this genetic change reduced DNA repair thus linking this mutation to increased skin cancer.

XPA Gene Mutations Resulting in Subtle Truncation of Protein in Xeroderma Pigmentosum Group A Patients with Mild Skin Symptoms

Comparisons of the clinical manifestations with gene mutations in patients with xeroderma pigmentosum group A (XPA) have suggested that those with mutations closer to the C-terminal coding region of the XPA gene have milder neurological and cutaneous symptoms. Here we report on four middle-aged, newly diagnosed Japanese XPA patients whose unusually mild symptoms, especially those affecting the skin, implicate a reduced association of a subtle defect in the C-terminus of XPA protein with skin lesions. All patients had a heterozygous G → C transversion at the splice acceptor site of XPA intron 3. We identified previously unreported heterozygous mutations in exon 6: a single-base insertion (690insT) in one patient and a four-base insertion (779insTT and 780insTT) in the other patients. These mutations led to the frameshift that created new premature termination codons, resulting in the production of truncated XPA proteins. They were longer than any previously reported truncated XPA protein, suggesting that the minimal cutaneous symptoms in these patients are due to a higher residual level of XPA protein activity and that the subtle defect in the C-terminus of XPA protein is more closely related to neurological impairment than to cutaneous abnormalities.

Hereditary Disorders with Defective Repair of UV-Induced DNA Damage

Nucleotide excision repair (NER) is an essential system for correcting ultraviolet (UV)—induced DNA damage. Lesions remaining in DNA due to reduced capacity of NER may result in cellular death, premature aging, mutagenesis and carcinogenesis of the skin. So, NER is an important protection against these changes. There are three representative genodermatoses resulting from genetic defects in NER: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). In Japan, CS is similarly rare but XP is more common and TTD is less common compared to Western countries. In 1998, we established the system for the diagnosis of these disorders and we have been performing DNA repair and genetic analysis for more than 400 samples since then. At present, there is no cure for any human genetic disorder. Early diagnosis and symptomatic treatment of neurological, ocular and dermatological abnormalities should contribute to prolonging life and elevating QOL in patients.

Dyschromatosis Symmetrica Hereditaria and Aicardi-Goutières Syndrome 6 Are Phenotypic Variants Caused by ADAR1 Mutations

nucleases such as transcription activator-like effector nucleases and an improved clustered, regularly interspaced, short palindromic repeat/Cas9 system or by decreasing the non-homologous end joining pathway to enhance HDR. Gene editing strategies using DSB-mediated HDR could also be used for gene correction of induced pluripotent stem cells from RDEB patient fibroblasts, allowing their redifferentiation into functionally corrected autologous keratinocytes, fibroblasts, and/or mesenchymal stromal cells. Gene-corrected induced pluripotent stem cells have also a strong therapeutic potential for other inherited genetic skin diseases such as junctional epidermolysis bullosa (Sebastiano et al., 2014; Umegaki-Arao et al., 2014) and xeroderma pigmentosum (Dupuy et al., 2013; Redondo et al., 2008).

Xeroderma pigmentosum complementation group F: Report of a case and review of Japanese patients

Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder characterized by extraordinary sensitivity to sunlight, resulting in cutaneous malignant tumors. Among XP, XP‐F presents relatively uniquely in Japanese. To clarify the characteristics of this group, we describe a case of XP‐F and review Japanese cases previously reported. A 50‐year‐old Japanese woman was referred to us with multiple, variously sized, light‐ or dark‐brown macules on the face and sunlight‐exposed extremities. She had experienced bulla formation with approximately 10 min of sunlight exposure during her elementary school years. Her parents had been first cousins, and her mother and sister had photosensitivity. She showed no neurological or developmental abnormalities. Ultraviolet (UV) irradiation testing revealed normal levels for minimal erythema dose with UV‐A and UV‐B. Sensitivity to UV‐C and DNA repair ability in the patients fibroblasts were indicated between that in normal individuals and that in an XP‐A patient. Complementation assay revealed that transfection of the XPF gene led most efficient DNA repair compared with the other XP genes. Therefore, the patient was diagnosed with XP‐F. Twenty‐three cases of Japanese patients (six males, 17 females) with XP‐F have been reported, including the present case. Our review suggested a relatively high prevalence of 50% (11/22) for cutaneous malignant tumors. A significant difference was evident in the mean age at first medical consultation between patients with cutaneous malignant tumors (53.6 years) and patients without such tumors (30.8 years). This suggests that cutaneous malignant tumors could occur in the age range of 30–50 years in XP‐F patients.

Prenatal diagnosis of xeroderma pigmentosum group A in Japan

We performed a prenatal diagnosis for 10 fetuses from nine unrelated Japanese xeroderma pigmentosum complementation group A (XP‐A) families. All parents had at least one XP‐A child (proband) with a homozygous founder mutation (IVS3‐1G>C) in the XPA gene. A genetic analysis was performed by a restriction enzyme; AlwNI fragment length polymorphism of polymerase chain reaction (PCR)‐amplified DNA, mostly from amniotic fluid (AF) and cultured cells established from AF. However, for the first family, we tried amniocentesis as well as chorionic villus sampling (CVS). Among the 10 cases, we confirmed the results of PCR‐based genetic diagnosis by post‐ultraviolet survival of amniotic cells in eight cases. Unfortunately, 6 weeks after CVS and 4 days after the amniocentesis in the first case we examined, the fetus died in utero, the reason for which remains unexplained. We prenatally determined two XP‐A cases, six XP‐A carriers and two wild‐type fetuses, which appears to be consistent with Mendel’s law.