Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

Unique skin changes in a case of Albright hereditary osteodystrophy caused by a rare GNAS1 mutation.

Albright hereditary osteodystrophy (AHO) is a syndrome of short stature, obesity, brachydactyly and subcutaneous calcifications with pseudohypoparathyroidism (PHP; leading to hypocalcaemia, hyperphosphataemia and elevated levels of parathyroid hormone, PTH). It was first described over 60 years ago. Since then, much has been learned about the aetiology of AHO which has been shown to be caused by heterozygous loss-of-function mutations within the GNAS1 gene. GNAS1 is subject to imprinting leading to phenotypic heterogeneity within kindreds with one mutation. Patients with AHO often present with symptoms of hypocalcaemia and/or with subcutaneous calcifications. The latter is thought to be the typical skin abnormality in AHO. We describe a family with AHO and hormone resistance (PHP type Ia) resulting from a rare mutation in GNAS1. The proband presented with small subcutaneous calcifications in the helix of the right ear and concentrated in a sharply demarcated zone of subcutaneous and dermal hypoplasia. This abnormality has so far not been described in patients with AHO. We speculate on the mechanism of dermal hypoplasia and resistance to PTH and suggest that subcutanous or dermal hypoplasia might be another feature which can be present in patients with AHO.