Germline mutation in ATR in autosomal- dominant oropharyngeal cancer syndrome.

ATR (ataxia telangiectasia and Rad3 related) is an essential regulator of genome integrity. It controls and coordinates DNA-replication origin firing, replication-fork stability, cell-cycle checkpoints, and DNA repair. Previously, autosomal-recessive loss-of-function mutations in ATR have been demonstrated in Seckel syndrome, a developmental disorder. Here, however, we report on a different kind of genetic disorder that is due to functionally compromised ATR activity, which translates into an autosomal-dominant inherited disease. The condition affects 24 individuals in a five-generation pedigree and comprises oropharyngeal cancer, skin telangiectases, and mild developmental anomalies of the hair, teeth, and nails. We mapped the disorder to a ∼16.8 cM interval in chromosomal region 3q22-24, and by sequencing candidate genes, we found that ATR contained a heterozygous missense mutation (c.6431A>G [p.Gln2144Arg]) that segregated with the disease. The mutation occurs within the FAT (FRAP, ATM, and TRRAP) domain-which can activate p53-of ATR. The mutation did not lead to a reduction in ATR expression, but cultured fibroblasts showed lower p53 levels after activation of ATR with hydroxyurea than did normal control fibroblasts. Moreover, loss of heterozygosity for the ATR locus was noted in oropharyngeal-tumor tissue. Collectively, the clinicopathological and molecular findings point to a cancer syndrome and provide evidence implicating a germline mutation in ATR and susceptibility to malignancy in humans.

African tick bite fever: a not-so-uncommon illness in international travelers.

BACKGROUND: African tick bite fever is a rickettsial illness that has recently emerged as a significant disease among international travelers. The vector is the Amblyomma tick, which is endemic to sub-Saharan Africa and parts of the eastern Caribbean. OBSERVATIONS: We describe a middle-aged woman who returned from a mission trip to Zimbabwe with an influenzalike illness and inoculation eschar; she also had a history of travel to a game farm. Biopsy revealed a histopathologic pattern consistent with an infectious pathogenesis. Immunohistochemical staining confirmed the presence of rickettsial organisms. In light of the patient's history, the clinical constellation of signs and symptoms, and the results of ancillary laboratory testing, a diagnosis of African tick bite fever was made. The patient was treated with doxycycline hydrochloride and had an uncomplicated course. CONCLUSIONS: This report further highlights the epidemiological and clinical features of African tick bite fever. With the increase in international travel, it is important to recognize the illness in those who have been to endemic countries and to counsel patients regarding preventive measures for planned travel.

Subacute cutaneous lupus erythematosus exacerbated or induced by chemotherapy.

BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE), characterized by nonscarring, photodistributed, annular or papulosquamous plaques, is occasionally induced by medication. It has been strongly associated with antihypertensive medications and terbinafine hydrochloride. OBSERVATION: We describe 3 women with breast cancer who developed SCLE-like eruptions after being administered doxorubicin hydrochloride and cyclophosphamide. Biopsy specimens of all 3 patients demonstrated an interface dermatitis. Treatment consisted of topical and/or systemic corticosteroids, photoprotection, and switching the chemotherapeutic regimens. CONCLUSIONS: Based on clinicopathologic correlation and timing of chemotherapy exposure, the patients were believed to have drug-induced SCLE. Although cutaneous eruption, pruritus, and photosensitivity are known adverse effects of doxorubicin, to our knowledge there has been only 1 previously reported case of doxorubicin-induced SCLE.