Publications by authors named "John J DiGiovanna"

84 Publications

Xeroderma Pigmentosum: A Model for Human Premature Aging.

J Invest Dermatol 2021 Jan 9. Epub 2021 Jan 9.

Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address:

Aging results from intrinsic changes (chronologic) and damage from external exposures (extrinsic) on the human body. The skin is ideal to visually differentiate their unique features. Inherited diseases of DNA repair, such as xeroderma pigmentosum (XP), provide an excellent model for human aging due to the accelerated accumulation of DNA damage. Poikiloderma, atypical lentigines, and skin cancers, the primary cutaneous features of XP, occur in the general population but at a much older age. Patients with XP also exhibit ocular changes secondary to premature photoaging, including ocular surface tumors and pterygium. Internal manifestations of premature aging, including peripheral neuropathy, progressive sensorineural hearing loss, and neurodegeneration, are reported in 25% of patients with XP. Internal malignancies, such as lung cancer, CNS tumors, and leukemia and/or lymphoma, occur at a younger age in patients with XP, as do thyroid nodules. Premature ovarian failure is overrepresented among females with XP, occurring 20 years earlier than in the general population. Taken together, these clinical findings highlight the importance of DNA repair in maintaining genomic integrity. XP is a unique model of human premature aging, which is revealing new insights into aging mechanisms.
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http://dx.doi.org/10.1016/j.jid.2020.11.012DOI Listing
January 2021

Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents.

Pediatr Dermatol 2021 Jan 10;38(1):164-180. Epub 2020 Nov 10.

Departments of Dermatology and Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Topical and systemic retinoids have long been used in the treatment of ichthyoses and other disorders of cornification. Due to the need for long-term use of retinoids for these disorders, often beginning in childhood, numerous clinical concerns must be considered. Systemic retinoids have known side effects involving bone and eye. Additionally, potential psychiatric and cardiovascular effects need to be considered. Contraceptive concerns, as well as the additive cardiovascular and bone effects of systemic retinoid use with hormonal contraception must also be deliberated for patients of childbearing potential. The Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group was formed to address these issues and to establish best practices regarding the use of retinoids in ichthyoses based on available evidence and expert opinion.
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http://dx.doi.org/10.1111/pde.14408DOI Listing
January 2021

A novel frameshift mutation in SOX10 causes Waardenburg syndrome with peripheral demyelinating neuropathy, visual impairment and the absence of Hirschsprung disease.

Am J Med Genet A 2020 05 9;182(5):1278-1283. Epub 2020 Mar 9.

NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Waardenburg syndrome (WS) is a group of genetic disorders associated with varying components of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and eyes. There exist four different WS subtypes, each defined by the absence or presence of additional features. One of the genes associated with WS is SOX10, a key transcription factor for the development of neural crest-derived lineages. Here we report a 12-year-old boy with a novel de novo SOX10 frameshift mutation and unique combination of clinical features including primary peripheral demyelinating neuropathy, hearing loss and visual impairment but absence of Hirschsprung disease and the typical pigmentary changes of hair or skin. This expands the spectrum of currently recognized phenotypes associated with WS and illustrates the phenotypic heterogeneity of SOX10-associated WS.
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http://dx.doi.org/10.1002/ajmg.a.61542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167353PMC
May 2020

Reproductive Health in Xeroderma Pigmentosum: Features of Premature Aging.

Obstet Gynecol 2019 10;134(4):814-819

National Human Genome Research Institute, National Institutes of Health, and the Laboratory of Cancer Biology and Genetics, Center for Cancer Research, and the Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Howard University Medical Center, Washington, DC.

Objective: To assess the age at menarche and menopause of women with xeroderma pigmentosum, a DNA repair disease with premature aging, in a longitudinal natural history study.

Methods: We conducted a natural history study that reviewed medical records for gynecologic and reproductive health of all female patients with xeroderma pigmentosum aged older than 9 years examined at the National Institutes of Health (NIH). We performed gynecologic and laboratory examinations on a subset of the patients. Women in a second subset, who could not be examined, were interviewed using a questionnaire. Women who were deceased or lost to follow-up formed a third subset.

Results: Sixty females with xeroderma pigmentosum aged older than 9 years (median 29 years, range 10-61 years) were evaluated at the NIH from 1971 to 2018. Of these 60, 31 had history, questionnaire, record review, and gynecologic evaluation; 14 had record review and questionnaire interview by telephone; and 15 had only NIH record review. Menarche in females with xeroderma pigmentosum occurred at a median age of 12.0 years (range 9-17 years), which was comparable with the U.S. general population. Among the 18 patients with menopause, the median age at menopause of 29.5 years (range 18-49.5 years) was more than 20 years younger than in the U.S. general population (52.9 years). Premature menopause (before age 40 years) occurred in 14 of the 45 (31%) women aged 18 years or older, and primary ovarian insufficiency was documented in nine of them. There were 32 live births among 21 of the women, five of whom subsequently developed premature menopause.

Conclusion: Females with xeroderma pigmentosum in our study had a normal age at menarche and were fertile but had increased incidence of premature menopause. Premature menopause, a symptom of premature aging, should be considered for gynecologic and reproductive health as well as implicating DNA repair in maintaining normal ovarian function.

Clinical Trial Registration: ClinicalTrials.gov, NCT00001813.
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http://dx.doi.org/10.1097/AOG.0000000000003490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768713PMC
October 2019

Predisposition to hematologic malignancies in patients with xeroderma pigmentosum.

Haematologica 2020 04 22;105(4):e144-e146. Epub 2019 Aug 22.

Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD

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http://dx.doi.org/10.3324/haematol.2019.223370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109711PMC
April 2020

Hydroa vacciniforme-like lymphoproliferative disorder: an EBV disease with a low risk of systemic illness in whites.

Blood 2019 06 7;133(26):2753-2764. Epub 2019 May 7.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Patients with classic hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) typically have high levels of Epstein-Barr virus (EBV) DNA in T cells and/or natural killer (NK) cells in blood and skin lesions induced by sun exposure that are infiltrated with EBV-infected lymphocytes. HVLPD is very rare in the United States and Europe but more common in Asia and South America. The disease can progress to a systemic form that may result in fatal lymphoma. We report our 11-year experience with 16 HVLPD patients from the United States and England and found that whites were less likely to develop systemic EBV disease (1/10) than nonwhites (5/6). All (10/10) of the white patients were generally in good health at last follow-up, while two-thirds (4/6) of the nonwhite patients required hematopoietic stem cell transplantation. Nonwhite patients had later age of onset of HVLPD than white patients (median age, 8 vs 5 years) and higher levels of EBV DNA (median, 1 515 000 vs 250 000 copies/ml) and more often had low numbers of NK cells (83% vs 50% of patients) and T-cell clones in the blood (83% vs 30% of patients). RNA-sequencing analysis of an HVLPD skin lesion in a white patient compared with his normal skin showed increased expression of interferon-γ and chemokines that attract T cells and NK cells. Thus, white patients with HVLPD were less likely to have systemic disease with EBV and had a much better prognosis than nonwhite patients. This trial was registered at www.clinicaltrials.gov as #NCT00369421 and #NCT00032513.
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http://dx.doi.org/10.1182/blood.2018893750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598378PMC
June 2019

Use of Big Data to Estimate Prevalence of Defective DNA Repair Variants in the US Population.

JAMA Dermatol 2019 01;155(1):72-78

Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Importance: Wide use of genomic sequencing to diagnose disease has raised concern about the extent of genotype-phenotype correlations.

Objective: To correlate disease-associated allele frequencies with expected and reported prevalence of clinical disease.

Design, Setting, And Participants: Xeroderma pigmentosum (XP), a recessive, cancer-prone, neurocutaneous disorder, was used as a model for this study. From January 1, 2017, to May 4, 2018, the Human Gene Mutation Database and a cohort of patients at the National Institutes of Health were searched and screened to identify reported mutations associated with XP. The clinical phenotype of these patients was confirmed from reports in the literature and National Institutes of Health medical records. The genetically predicted prevalence of disease based on frequency of known pathogenic mutations was compared with the prevalence of patients clinically diagnosed with phenotypic XP. Exome sequencing of more than 200 000 alleles from the Genome Aggregation Database, the National Cancer Institute Division of Cancer Epidemiology and Genetics database of healthy controls, and an Inova Hospital Study database was used to investigate the frequencies of these mutations in the general population.

Main Outcomes And Measures: Listing of all reported mutations associated with XP, their frequencies in 3 large exome sequence databases, determination of the number of patients in the United States with XP using modeling equations, and comparison of the observed and reported numbers of patients with XP with specific mutations.

Results: A total of 156 pathogenic missense and nonsense mutations associated with XP were identified in the National Institutes of Health cohort and the Human Gene Mutation Database. The Genome Aggregation Database provided frequency data for 65 of these mutations, with a total allele frequency of 1.13%. The XPF (ERCC4) mutation, p.P379S, had an allele frequency of 0.4%, and the XPC mutation, p.P334H, had an allele frequency of 0.3%. With the Hardy-Weinberg equation, it was determined that there should be more than 8000 patients who are homozygous for these mutations in the United States. In contrast, only 3 patients with XP were reported as having the XPF mutation, and 1 patient was reported as having the XPC mutation.

Conclusions And Relevance: The findings from this study suggest that clinicians should approach large genomic databases with caution when trying to correlate the clinical implications of genetic variants with the prevalence of disease risk. Unsuspected mutations in known genes with a predisposition for skin cancer may be responsible for some of the high frequency of skin cancers in the general population.
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http://dx.doi.org/10.1001/jamadermatol.2018.4473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439575PMC
January 2019

Variant subtype of xeroderma pigmentosum diagnosed in a 77-year-old woman.

JAAD Case Rep 2018 Nov 14;4(10):1074-1076. Epub 2018 Nov 14.

Division of Dermatology, Dell Medical School, University of Texas at Austin, Austin, Texas.

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http://dx.doi.org/10.1016/j.jdcr.2018.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250902PMC
November 2018

Four-dimensional, dynamic mosaicism is a hallmark of normal human skin that permits mapping of the organization and patterning of human epidermis during terminal differentiation.

PLoS One 2018 13;13(6):e0198011. Epub 2018 Jun 13.

Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.

Recent findings of mosaicism (DNA sequence variation) challenge the dogma that each person has a stable genetic constitution. Copy number variations, point mutations and chromosome abnormalities in normal or diseased tissues have been described. We studied normal skin mosaicism of a single nucleotide polymorphism (SNP) [rs1426654, p.Thr111Ala] in SLC24A5, an ion transporter gene. This SNP is unusual in that more than 90% of people of European descent have homozygous germline A/A alleles, while more than 90% of East Asians and Blacks have homozygous germline G/G alleles. We found mosaicism in neonatal foreskins as well as in 69% of nearly 600 skin surface scraping samples from 114 donors of different ages. Strikingly, donors with germline (buccal or blood) A/A, A/G or G/G genotypes had all three sequences (A/A, A/G or G/G) in the skin surface scrapings. SNP sequence differences extended within the epidermis in the vertical dimension from basal cell layer to the stratum corneum at the surface, as well as across the two-dimensions of the skin surface. Furthermore, repeated scrapings in the same location revealed variation in the sequences in the same individuals over time, adding a fourth dimension to this variation. We then used this mosaicism to track the movement of epidermal cells during normal differentiation and characterize the patterning of epidermal cells during terminal differentiation. In this coordinated proliferation model of epidermal differentiation, the skin surface is alternatively populated by synchronous, cycling of waves of cells, with each group having a different DNA sequence. These groups of cells abruptly flatten into large sheets at the surface providing patches of uniform SNP sequence. This four-dimensional mosaicism is a normal, previously unrecognized form of dynamic mosaicism in human skin.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198011PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999106PMC
December 2018

Neurodegeneration as the presenting symptom in 2 adults with xeroderma pigmentosum complementation group F.

Neurol Genet 2018 Jun 8;4(3):e240. Epub 2018 Jun 8.

Department of Neurology (N.M.S., M.D.G.), University of California San Francisco, CA; Laboratory of Cancer Biology and Genetics (J.J.D., K.H.K.), Center for Cancer Research, National Cancer Institute, National Institutes of Health; NIH Undiagnosed Diseases Program (C.G., R.G., M.C.V.M., W.A.G., C.T.), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; and Department of Molecular Medicine (M.J.Y., E.A.W., L.J.N.), Center on Aging, The Scripps Research Institute, Jupiter, FL.

Objective: To describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting.

Methods: We report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of 2 middle-aged women with progressive neurodegeneration ultimately diagnosed with XP-F.

Results: Both patients presented with adult-onset progressive neurologic deterioration involving chorea, ataxia, hearing loss, cognitive deficits, profound brain atrophy, and a history of skin photosensitivity, skin freckling, and/or skin neoplasms. We identified compound heterozygous pathogenic mutations in and confirmed deficient NER capacity in skin fibroblasts from both patients.

Conclusions: These cases illustrate the role of NER dysfunction in neurodegeneration and how adult-onset neurodegeneration could be the major symptom bringing XP-F patients to clinical attention. XP-F should be considered by neurologists in the differential diagnosis of patients with adult-onset progressive neurodegeneration accompanied by global brain atrophy and a history of heightened sun sensitivity, excessive freckling, and skin malignancies.
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http://dx.doi.org/10.1212/NXG.0000000000000240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994703PMC
June 2018

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

J Clin Invest 2018 07 11;128(7):3041-3052. Epub 2018 Jun 11.

Translational Autoinflammatory Disease Section, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.

Background: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.

Methods: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.

Results: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.

Conclusion: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.

Trial Registration: ClinicalTrials.gov NCT01724580 and NCT02974595.

Funding: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.
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http://dx.doi.org/10.1172/JCI98814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026004PMC
July 2018

Chemoprevention of Basal and Squamous Cell Carcinoma With a Single Course of Fluorouracil, 5%, Cream: A Randomized Clinical Trial.

JAMA Dermatol 2018 02;154(2):167-174

Cooperative Studies Program Central Office, Washington, DC.

Importance: Keratinocyte carcinoma (ie, cutaneous basal and squamous cell carcinoma) is the most common cancer in the United States.

Objective: To determine whether topical fluorouracil could prevent surgically treated keratinocyte carcinoma.

Design, Setting, And Participants: The Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial was a randomized, double-blind, placebo-controlled trial of topical fluorouracil for chemoprevention of keratinocyte carcinoma. Participants were recruited from May 2009 to September 2011 from 12 Veterans Affairs medical centers and followed until June 30, 2013. Participants were veterans (n = 932) with a history of at least 2 keratinocyte carcinomas in the past 5 years; almost all were white males and the median age was 70 years.

Interventions: Application of fluorouracil, 5%, (n = 468) or vehicle control cream (n = 464) to the face and ears twice daily for 2 to 4 weeks upon randomization.

Main Outcomes And Measures: Surgically treated keratinocyte, basal cell, and squamous cell carcinoma risk on the face and ears in the first year after enrollment; and time to first surgically treated keratinocyte, basal cell, and squamous cell carcinoma. The a priori hypothesis was that fluorouracil would be effective in preventing these cancers.

Results: Of 932 participants (916 men [98%]; 926 white [99%]; median age, 70 years), 299 developed a basal cell carcinoma end point (95 in year 1) and 108 developed a squamous cell carcinoma end point (25 in year 1) over 4 years (median follow-up, 2.8 years). Over the entire study, there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma. During the first year, however, 5 participants (1%) in the fluorouracil group developed a squamous cell carcinoma vs 20 (4%) in the control group, a 75% (95% CI, 35%-91%) risk reduction (P = .002). The 11% reduction in basal cell carcinoma risk during year 1 (45 [10%] in the fluorouracil group vs 50 [11%] in the control group) was not statistically significant (95% CI, 39% reduction to 31% increase), nor was there a significant effect on keratinocyte carcinoma risk. However, a reduction in keratinocyte carcinomas treated with Mohs surgery was observed.

Conclusions And Relevance: A conventional course of fluorouracil to the face and ears substantially reduces surgery for squamous cell carcinoma for 1 year without significantly affecting the corresponding risk for basal cell carcinoma.

Trial Registration: clinicaltrials.gov Identifier: NCT00847912.
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http://dx.doi.org/10.1001/jamadermatol.2017.3631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839275PMC
February 2018

Recurrent scarring papulovesicular lesions on sun-exposed skin in a 22-year-old man.

J Am Acad Dermatol 2018 03 28;78(3):637-642. Epub 2017 Sep 28.

Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

KEY TEACHING POINTS.
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http://dx.doi.org/10.1016/j.jaad.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815928PMC
March 2018

5-Fluorouracil for Actinic Keratosis Treatment and Chemoprevention: A Randomized Controlled Trial.

J Invest Dermatol 2017 06;137(6):1367-1370

Center for Dermatoepidemiology-111D, Veterans Affairs Medical Center, Providence, Rhode Island, USA; Department of Dermatology, Brown University, Providence, Rhode Island, USA.

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http://dx.doi.org/10.1016/j.jid.2016.12.029DOI Listing
June 2017

Basic Science Insights into Clinical Puzzles.

Dermatol Clin 2017 Jan;35(1):ix-x

DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 37 Room 4002, Bethesda, MD 20892-4262, USA. Electronic address:

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http://dx.doi.org/10.1016/j.det.2016.10.001DOI Listing
January 2017

GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy.

Am J Hum Genet 2016 Apr 17;98(4):627-42. Epub 2016 Mar 17.

Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy. Electronic address:

The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEβ). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEα and TFIIEβ) as well as decreased phosphorylation of TFIIEα in cells from both children. Interestingly, decreased phosphorylation of TFIIEα was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP.
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http://dx.doi.org/10.1016/j.ajhg.2016.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833217PMC
April 2016

Cutaneous adverse events in multiple sclerosis patients treated with daclizumab.

Neurology 2016 Mar 3;86(9):847-55. Epub 2016 Feb 3.

From the Neuroimmunology Clinic (I.C., J.O.) and the Neuroimmunological Diseases Unit (B.B.), National Institute of Neurological Disorders and Stroke, and the Laboratory of Pathology (C.-C.L., M.R.) and the Dermatology Branch (E.W.C., J.J.D.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda; and Department of Neurology (K.F.), Johns Hopkins School of Medicine, Baltimore, MD.

Objective: To analyze the spectrum and mechanisms of cutaneous adverse events (AEs) in patients with multiple sclerosis treated with daclizumab high-yield process (DAC-HYP).

Methods: A total of 31 participants in an institutional review board-approved open-label phase I study of DAC-HYP (NCT01143441) were prospectively evaluated over 42 months for development of cutaneous AEs. Participants provided written informed consent. Fifteen participants were naive to anti-CD25 therapy (cohort B), while 16 had received daclizumab (Zenapax; Hoffmann-La Roche) IV for 4-9 years (mean 5.8 years) prior to enrollment (cohort A). Immunohistochemistry was performed on pretreatment and posttreatment skin biopsies of normal-appearing skin (cohort B only) and on lesional biopsies in participants presenting with rash (both cohorts).

Results: Cutaneous AEs occurred in 77% of patients, the majority presenting with patches of eczema requiring no treatment. Moderate to severe rash developed in 6 participants (19%) and required discontinuation of DAC-HYP in 4 (13%). More severe rashes presented psoriasiform phenotype, but lesional biopsies lacked features of either psoriasis or drug hypersensitivity eruptions. Instead, irrespective of clinical severity, lesional biopsies showed nonspecific features of eczematous dermatitis, but with prominent CD56+ lymphocytic infiltrates. Pretreatment and posttreatment biopsies of normal-appearing skin demonstrated no histopathologic changes.

Conclusions: Observed cutaneous AEs are likely related to the immunomodulatory effects DAC-HYP exerts on innate lymphoid cells, including natural killer cells. Vigilance and timely management of skin reactions may prevent treatment discontinuation in participants with severe rash.
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http://dx.doi.org/10.1212/WNL.0000000000002417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793779PMC
March 2016

Comedonal and Cystic Fibrofolliculomas in Birt-Hogg-Dube Syndrome.

JAMA Dermatol 2015 Jul;151(7):770-4

Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland5Section Editor, "The Cutting Edge," JAMA Dermatology.

Importance: The differential diagnosis of extensive open comedones includes inherited genetic syndromes and several acquired conditions. Birt-Hogg-Dube syndrome (BHD) is not typically included in the differential diagnosis of syndromes with comedonal lesions. Given the potentially life-threatening systemic complications associated with BHD, early recognition and diagnosis of the condition is important.

Observations: We describe comedonal or cystic fibrofolliculomas in 4 patients with BHD. Cutaneous lesions were identified on the face, neck, chest, and abdomen.

Conclusions And Relevance: Comedonal or cystic fibrofolliculomas are a variant of fibrofolliculomas that have not previously been well characterized in patients with BHD and represent a novel diagnostic clue to its early detection and diagnosis. Expanding the phenotypic features of BHD facilitates earlier diagnosis of the syndrome, which allows for early surveillance of renal cancer in affected patients as well as disease screening in their relatives.
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http://dx.doi.org/10.1001/jamadermatol.2015.0215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701978PMC
July 2015

Readthrough of stop codons by use of aminoglycosides in cells from xeroderma pigmentosum group C patients.

Exp Dermatol 2015 Apr 23;24(4):296-7. Epub 2015 Mar 23.

Dermatology Branch, NCI, Bethesda, MD, USA.

Readthrough of premature termination (stop) codons (PTC) is a new approach to treatment of genetic diseases. We recently reported that readthrough of PTC in cells from some xeroderma pigmentosum complementation group C (XP-C) patients could be achieved with the aminoglycosides geneticin or gentamicin. We found that the response depended on several factors including the PTC sequence, its location within the gene and the aminoglycoside used. Here, we extended these studies to investigate the effects of other aminoglycosides that are already on the market. We reasoned that topical treatment could deliver much higher concentrations of drug to the skin, the therapeutic target, and thus increase the therapeutic effect while reducing renal or ototoxicity in comparison with systemic treatment. Our prior clinical studies indicated that only a few percent of normal XPC expression was associated with mild clinical disease. We found minimal cell toxicity in the XP-C cells with several aminoglycosides. We found increased XPC mRNA expression in PTC-containing XP-C cells with G418, paromomycin, neomycin and kanamycin and increased XPC protein expression with G418. We conclude that in selected patients with XP, topical PTC therapy can be investigated as a method of personalized medicine to alleviate their cutaneous symptoms.
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http://dx.doi.org/10.1111/exd.12655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334769PMC
April 2015

Cutaneous adverse effects associated with the tyrosine-kinase inhibitor cabozantinib.

JAMA Dermatol 2015 Feb;151(2):170-7

Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland4section editor, JAMA Dermatology.

Importance: Cabozantinib S-malate is a vascular endothelial growth factor receptor 2, c-MET, and RET multitargeted tyrosine kinase inhibitor that has antiangiogenic and antitumorigenic properties with potential efficacy for the treatment of several cancers. Cutaneous reactions, one of the most frequently observed adverse effects associated with tyrosine kinase inhibitors, can significantly affect patients' quality of life and drug adherence and represent a major therapeutic challenge to maximizing the efficacy of targeted cancer therapy.

Objective: To describe the frequency and spectrum of skin reactions in patients with urothelial carcinoma receiving cabozantinib as monotherapy.

Design, Setting, And Participants: A single-institution study at the Clinical Research Center at the National Institutes of Health included 41 consecutive adults with metastatic, progressive urothelial carcinoma enrolled in a National Cancer Institute open-label, nonrandomized, phase 2 clinical trial. Patients receiving cabozantinib were evaluated for the development of skin reactions at each treatment visit from October 2012 to June 2014 by the primary oncology team and referred for dermatologic evaluation as appropriate.

Main Outcomes And Measures: A detailed history, full-body physical examination, and clinical photographs of cutaneous lesions were obtained.

Results: Of 41 consecutive patients who received cabozantinib, 30 (73%) developed 1 or more cutaneous toxic effects. Adverse events included hand-foot skin reaction (22 [54%]), generalized pigment dilution and/or hair depigmentation (18 [44%]), xerosis (8 [20%]), scrotal erythema/ulceration (6 [15%]), and nail splinter hemorrhages (5 [12%]). Eighteen patients (44%) had 2 or more cutaneous adverse events. Reactions developed in 17 of 30 patients (57%) during the first month of cabozantinib treatment and in 24 of 30 (80%) by the second month. Of patients with skin toxic effects, dose reduction was required for symptom management in 9 of 30 patients (30%), and treatment discontinuation was required in 4 of 30 (13%).

Conclusions And Relevance: Cabozantinib monotherapy is associated with 1 or more cutaneous adverse events in most patients. Early detection and prompt treatment may increase patients' adherence to tyrosine kinase inhibitor therapy.

Trial Registration: clinicaltrials.gov Identifier: NCT01688999.
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http://dx.doi.org/10.1001/jamadermatol.2014.2734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776420PMC
February 2015

Global contributions to the understanding of DNA repair and skin cancer.

J Invest Dermatol 2014 Oct 10;134(e1):E8-17. Epub 2014 Oct 10.

Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1038/skinbio.2014.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334767PMC
October 2014

Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype.

J Invest Dermatol 2015 Mar 7;135(3):734-741. Epub 2014 Oct 7.

Dermatology Branch, Center for Cancer Research, National Cancer Institute National Institutes of Health, Bethesda, MD USA.

Trichothiodystrophy (TTD) is a rare multisystem disorder, characterized by sulfur-deficient hair with alternating dark and light "tiger tail" banding on polarized light microscopy. TTD is caused by mutations in DNA repair/transcription genes XPD, XPB or TTDA, and in TTDN1, a gene of unknown function. Although most of the TTD patients are photosensitive, patients with TTDN1 mutations were reported to be nonphotosensitive. We followed a cohort of 36 TTD patients from 2001 to 2013. We describe five patients from four families with defects in the TTDN1 gene: four had no photosensitivity, and one patient exhibited cutaneous burning. Deep phenotyping of our cohort revealed differences between the patients with and without TTDN1 mutations. Delayed bone age and seizure disorders were overrepresented in the TTDN1 group (P=0.009 and P=0.024, respectively), whereas some characteristic TTD clinical, laboratory, and imaging findings were absent. The three oldest TTDN1 patients displayed autistic behaviors in contrast to the characteristic friendly, socially interactive personality in the other patients. DNA sequencing revealed deletion mutations in TTDN1 ranging in size from a single base pair to over 120 kb. These data identify a distinct phenotype relationship in TTD caused by TTDN1 mutations and suggest a different mechanism of disease.
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http://dx.doi.org/10.1038/jid.2014.440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530629PMC
March 2015

Forty years of research on xeroderma pigmentosum at the US National Institutes of Health.

Photochem Photobiol 2015 Mar-Apr;91(2):452-9. Epub 2015 Jan 8.

Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

In 1968, Dr. James Cleaver reported defective DNA repair in cultured cells from patients with xeroderma pigmentosum. This link between clinical disease and molecular pathophysiology has sparked interest in understanding not only the clinical characteristics of sun sensitivity, damage and cancer that occurred in XP patients but also the mechanisms underlying the damage and repair. While affected patients are rare, their exaggerated UV damage provides a window into the workings of DNA repair. These studies have clarified the importance of a functioning DNA repair system to the maintenance of skin and neurologic health in the general population. Understanding the role of damage in causing cancer, neurologic degeneration, hearing loss and internal cancers provides an opportunity for prevention and treatment. Characterizing complementation groups pointed to the importance of different underlying genes. Studying differences in cancer age of onset and underlying molecular signatures in cancers occurring either in XP patients or the general population has led to insights into differences in carcinogenic mechanisms. The accelerated development of cancers in XP has been used as a model to discover new cancer chemopreventive agents. An astute insight can be a "tipping point" triggering decades of productive inquiry.
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http://dx.doi.org/10.1111/php.12345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355260PMC
September 2015

Growth and nutrition in children with trichothiodystrophy.

J Pediatr Gastroenterol Nutr 2014 Oct;59(4):458-64

*Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases †DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Objectives: Trichothiodystrophy (TTD) is a rare autosomal recessive disorder of DNA repair and transcription. Patients have multisystem abnormalities, including alterations in growth and development. This report characterizes the growth and nutritional status of a cohort of children with TTD.

Methods: Twenty-five patients with TTD were evaluated through a natural history study of patients with DNA repair diseases at the National Institutes of Health. Mean length of follow-up was 2.7 years. Retrospective and prospective data on nutritional status and height/weight were collected.

Results: In general, patients with TTD had considerable abnormalities in growth, with a mean height-for-age z score of -2.75 and a mean weight-for-age z score of -2.60 at baseline clinical evaluation. The median weight-for-length at baseline was, however, 50th percentile and indicators of adequate nutrition such as serum albumin, hemoglobin, and vitamins D and B12 were largely within normal limits. Changes in growth parameters as children aged were characterized by further separation from standard growth curves (change height-for-age z score/year [-0.18 ± 0.42] and weight-for-age z score/year [-0.36 ± 0.51]). Patients who died during follow-up (n = 5) had significantly lower standardized height (P = 0.03) and weight (P = 0.006), weight-for-length (<0.0001), and higher heart rates (P = 0.02) compared with the remainder of the cohort.

Conclusions: Children with TTD have markedly diminished weight-for-age and height-for-age relative to reference populations. The cause for this stunted growth remains unclear but does not appear to be related to poor nutrient absorption or malnutrition.
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http://dx.doi.org/10.1097/MPG.0000000000000458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176511PMC
October 2014

Rapid development of migratory, linear, and serpiginous lesions in association with immunosuppression.

J Am Acad Dermatol 2014 Jun;70(6):1130-4

DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

A 78-year-old Bulgarian woman presented to the National Institutes of Health (NIH) with a diagnosis of poorly differentiated metastatic carcinoma of unknown origin. The prior month she had been seen at a hospital in Bulgaria for weight loss and a right inguinal mass. NIH pathology review confirmed a poorly differentiated carcinoma with extensive necrosis suggesting squamous cell carcinoma. She was enrolled in a treatment trial at NIH with metastatic disease invading the lungs and lymph nodes (mediastinum, abdomen, and pelvis) and a chemotherapy regimen was started of gemcitabine, carboplatin, and lenalidomide with dexamethasone as an antiemetic. The patient returned on day 8, and a rash of 2 days duration was noted. Immediately before arriving at the dermatology clinic, she developed altered mental status with aphasia and was admitted for neurologic observation. The altered mental status resolved and evaluation revealed only small-vessel ischemia. The patient was also experiencing diarrhea and was found to have elevated transaminases (4- to 7-fold over normal). Chemotherapy was held because of the transaminase abnormalities and altered mental status. The following day, the patient was seen by dermatology for a progressive asymptomatic eruption.
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http://dx.doi.org/10.1016/j.jaad.2013.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024165PMC
June 2014

High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.

Pigment Cell Melanoma Res 2014 May 21;27(3):454-64. Epub 2014 Feb 21.

Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Division of Dermatology, Graduate School of Medicine, Kobe University, Kobe, Japan.

We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population.
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http://dx.doi.org/10.1111/pcmr.12226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309892PMC
May 2014

Living with xeroderma pigmentosum: comprehensive photoprotection for highly photosensitive patients.

Photodermatol Photoimmunol Photomed 2014 Apr-Jun;30(2-3):146-52. Epub 2014 Feb 19.

Dermatology Branch, Center for Cancer Research, National Institutes of Health, National Cancer Institute, Bethesda, MD, USA.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease of deoxyribonucleic acid (DNA) repair with ultraviolet (UV) radiation sensitivity and a 10 000-fold increased risk of skin cancer. Symptoms include: freckle-like pigmentation in sun-exposed skin before age 2 years, severe burns after minimal sun exposure (50% of patients) and damage to exposed surfaces of the eyes with loss of vision and ocular cancer. About 25% of patients develop a progressive neurodegeneration. The combination of an inherited inability to repair UV-induced DNA damage and environmental exposure to UV must occur for cutaneous and ocular symptoms to develop. There is no cure for XP, but many of its manifestations may be reduced or prevented through consistent UV protection; thus XP serves as a model for sun protection of patients with marked photosenstivity. Sun protective clothing including hats, sunglasses and face shields, sun screen lotions and avoidance of environmental sources of UV are cornerstones of prevention of skin and eye damage and cancer. Although XP is a serious disease with the potential for limitation of life expectancy, XP patients can live active lives while at the same time avoiding UV.
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http://dx.doi.org/10.1111/phpp.12108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334764PMC
October 2014