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.

Oxalosis involving the skin: case report and literature review.

BACKGROUND: The primary hyperoxalurias are a group of rare autosomal recessive metabolic disorders associated with abnormal overproduction of serum oxalate and subsequent deposition in tissue. Most patients present at an early age with recurrent urolithiasis and renal failure. Vascular deposition of oxalate-producing skin manifestations, such as livedo reticularis, acrocyanosis, peripheral gangrene, and ulcerations, is typical of the primary hyperoxalurias. OBSERVATIONS: We present the case of a 38-year-old woman with end-stage renal disease receiving hemodialysis with progressive skin changes, including livedo reticularis, superficial eschars, and brawny, woody fibrosis of her extremities, who was clinically suspected to have calciphylaxis or nephrogenic systemic fibrosis. Cutaneous biopsy specimens revealed rectangular, birefringent, yellowish-brown, polarizable crystalline material suggestive of oxalate within the dermis, subcutis, and medium-size vessels along with areas of focal epidermal and superficial dermal necrosis. Her subsequent medical history was obtained and was suggestive of a diagnosis of primary hyperoxaluria. CONCLUSIONS: This case highlights the variability of clinical presentations in primary hyperoxaluria and that the disease can be diagnosed in adulthood. In addition, this case demonstrates that hyperoxaluria should be included in the differential diagnosis of calciphylaxis and nephrogenic systemic fibrosis.

Mid-dermal elastolysis in a patient undergoing chronic hemodialysis.

Mid-dermal elastolysis (MDE) is a rare acquired disorder of unknown etiology that typically presents as discrete patches of wrinkling over the trunk and arms or as perifollicular papules in the same distribution. The histopathologic finding of a bandlike loss of elastic tissue localized to the mid dermis is diagnostic. Our patient presented with atypical clinical features of urticarial papules and plaques that were histopathologically diagnostic of MDE. To our knowledge, the atypical presentation of MDE and association with hemodialysis have not been described. Furthermore, we believe matrix metalloproteinase (MMP) dysfunction to be involved in the pathogenesis of the disease.

Nodular primary localized cutaneous amyloidosis after trauma: a case report and discussion of the rate of progression to systemic amyloidosis.

Nodular primary localized cutaneous amyloidosis (NPLCA) has been associated with progression to systemic amyloidosis. The reported estimate of 50% progression to systemic amyloidosis has come under scrutiny as recent studies have suggested a significantly lower rate. Still, it is essential to consider systemic amyloidosis after making the diagnosis of NPLCA and to follow up patients longitudinally for possible progression to systemic disease. We present a case of a 24-year-old woman with NPLCA with onset after traumatic injury, review the literature, and discuss the proposed rate of progression of NPLCA to systemic amyloidosis.

Cutaneous nephrology.

There are numerous cutaneous findings that may be related to coexistent renal disease. An astute clinician may use careful skin examination to make early diagnosis of renal conditions in some cases, and institute appropriate therapy as soon as indicated.