John J DiGiovanna

Patients with xeroderma pigmentosum (XP) have a 1,000-fold increase in ultraviolet (UV)-induced skin cancers while trichothiodystrophy (TTD) patients, despite mutations in the same genes, ERCC2 (XPD) or ERCC3 (XPB), are cancer-free. Unlike XP cells, TTD cells have a nearly normal rate of removal of UV-induced 6-4 photoproducts (6-4PP) in their DNA and low levels of the basal transcription factor, TFIIH. We examined seven XP, TTD, and XP/TTD complex patients and identified mutations in ...

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 ...

Erythrokeratodermia variabilis is an autosomal dominant genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The disorder maps to a cluster of connexin genes on chromosome 1p34-p35.1 and, in a subset of families, results from mutations in the gene GJB3 encoding the gap junction protein connexin-31 (Cx31). A recent report suggested the involvement of another connexin gene (GJB4) in the ...

The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of ...

Nevoid basal cell carcinoma syndrome (NBCC; Gorlin syndrome), an autosomal dominant disorder linked to 9q22.3-q31, and caused by mutations in PTC, the human homologue of the Drosophila patched gene, comprises multiple basal cell carcinomas, keratocysts of the jaw, palmar/plantar pits, spine and rib anomalies and calcification of the falx cerebri. We reviewed the findings on 105 affected individuals examined at the NIH since 1985. The data included 48 males and 57 females ranging in age ...

PURPOSE: Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal-dominant disorder characterized by multiple basal cell carcinomas, jaw cysts, palmar/plantar pits, calcification of the falx cerebri, and spine and rib anomalies. NBCCS is due to mutations in PTCH1, the human homologue of the Drosophila segment polarity gene patched. Mutations are detected in approximately 60% to 85% of individuals tested by sequencing of PTCH1; therefore, clinical examination and x-rays remain ...

Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least eight overlapping phenotypes. The clinical features of these patients have some similarities but also have marked ...

BACKGROUND: Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification, typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology.

OBJECTIVE: We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses.

METHODS: The classification ...

Keratitis-ichthyosis-deafness syndrome (KID) is a rare ectodermal dysplasia characterized by vascularizing keratitis, profound sensorineural hearing loss (SNHL), and progressive erythrokeratoderma, a clinical triad that indicates a failure in development and differentiation of multiple stratifying epithelia. Here, we provide compelling evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene, GJB2. In each of 10 patients with KID, we identified a point ...

Keratinocyte carcinoma (KC) is the most common cancer in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. Topical tretinoin has been used for KC chemoprevention, although this use is unproven. Hence, we conducted the randomized Veterans Affairs Topical Tretinoin Chemoprevention Trial of high-dose topical tretinoin for KC prevention. We randomized 1,131 patients to topical 0.1% tretinoin or a matching ...

Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. Unlike other hereditary disorders associated with cancer, it features widespread developmental defects. To investigate the possibility that the syndrome is caused by mutation in a tumor suppressor gene, we searched for loss of heterozygosity in 16 sporadic basal cell carcinomas, 2 hereditary basal cell carcinomas, and 1 hereditary ovarian ...

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: ...

To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma ...

About 12% of human genetic disorders involve premature termination codons (PTCs). Aminoglycoside antibiotics have been proposed for restoring full-length proteins by readthrough of PTC. To assess the efficiency of readthrough, we selected homozygous and compound heterozygous skin fibroblasts from xeroderma pigmentosum (XP) patients with different PTCs in the XPC DNA repair gene. XP patients have a nucleotide excision repair defect and a 10,000-fold increased risk of UV-induced skin ...