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.

Leukaemia cutis in a patient treated for breast cancer.

A 47-year-old woman with a history of breast cancer presented with eruptive cutaneous nodules on the trunk and extremities. Treatment for her breast cancer had included surgery, radiation and chemotherapy with doxorubicin and cyclophosphamide. Biopsy of the skin lesions revealed leukaemia cutis, which led to the discovery of acute myelogenous leukaemia. This was felt to be primarily induced by doxorubicin. Treatment included induction chemotherapy in preparation for a bone marrow transplant, which resulted in the disappearance of the cutaneous lesions. However, the patient later succumbed to her leukaemia.

Therapy-related leukaemia cutis: a review.

Leukaemia cutis following chemotherapy for a malignancy is a multifactorial process that is dependent on the chemotherapeutic agent used, the dosing regimen, and the cumulative dose as well as potential contributing therapies such as radiation and possibly even hematopoietic support from granulocyte colony stimulating factor. In the right combination and in a patient with a conducive milieu of epigenetic factors, leukaemia can develop as a treatment complication. Leukaemia cutis is the specific infiltration of the skin by leukaemic cells and occurs most commonly when the underlying leukaemia is an acute myeloid leukaemia. Although it is well reviewed in the literature as a result of primary leukaemia, leukaemia cutis has only very rarely been reported in association with therapy-induced leukaemia. This article reviews the factors that contribute to therapy-related leukaemia and the development of leukaemia cutis.

Dystrophic epidermolysis bullosa with one dominant and one recessive mutation of the COL7A1 gene in a child with deafness.

Dystrophic epidermolysis bullosa can be inherited in autosomal dominant and recessive forms, the former usually expressed as a milder phenotype, although mild forms of recessive dystrophic epidermolysis bullosa can occur. We present a patient who was found to be a compound heterozygote, inheriting a dominant mutation from his father and a recessive mutation from his mother, resulting in a clinically severe case of dystrophic epidermolysis bullosa. Mutations in the gene for collagen VII (COL7A1) have been documented in both types of dystrophic epidermolysis bullosa. Our patient has also been diagnosed with bilateral auditory neuropathy, a disorder coincidentally also mapped to a nearby gene on chromosome 3p21 (the transmembrane inner ear expressed gene, TMIE).

Dystrophic calcinosis cutis in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a genetic disorder in which elastic fibers become calcified with prominent cutaneous, ocular, and cardiovascular features. Calcinosis cutis is an acquired disorder of calcium deposition in cutaneous tissues that occurs as one of the following forms: dystrophic, metastatic, idiopathic, and iatrogenic. We report a case of a woman with PXE who developed widespread dystrophic calcinosis cutis in areas affected by PXE. Although tumoral calcification and nephrolithiasis have been reported in patients with PXE, only one other case in the English-language literature of PXE and calcinosis cutis has been reported and this case was characterized by small, milia-like papules on the front of the neck, without significant discomfort, whereas our patient had widespread involvement that was very painful and pruritic. On 6-month follow-up, this patient had only mild improvement after treatment with an anti-itch lotion and aluminum hydroxide, with which she was noncompliant.