Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next‐generation sequencing

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.     

Breast Cancer and Non‐Hodgkin Lymphoma in a Young Male with Cowden Syndrome

Male breast cancer (MBC) is unusual, especially in young adults. Most cases of MBC as a secondary malignancy relate to the previous treatment with ionizing radiation. MBC can be associated with mutations in hereditary cancer predisposition syndrome genes (i.e., BRCA2); however, no such association has been reported in patients with Cowden syndrome (involving the phosphatase and tensin homolog [PTEN] gene). We describe a patient with Cowden syndrome who was initially diagnosed with B‐cell lymphoblastic lymphoma at the age of 7 years, then MBC at the age of 31 years, and never received radiation therapy.     

Pearls of wisdom: Practical application of the Pearls series

Scores of ASHRM members have collaborated to produce the Pearls Series, a set of pocket guides on topics of interest for not only risk managers but also administrators, clinicians, and board members. The succinct format facilitates the dissemination of pertinent information to a wide audience. Risk managers should be knowledgeable of the Pearls topics, understand how to develop appropriate metrics, and manage the monitoring and performance improvement aspects that are critical to ensuring successful knowledge transfer.     

Newborn screening: New opportunities and new challenges

Newborn screening is an old technique for early detection of problems and health promotion. In recent times, genetic breakthroughs have created the possibility of testing for many more newborn conditions. Some states are mandating as many as 20 to 30 tests. This article will review newborn screening, the state of the art, and some of the ethical questions that our technology is raising. Copyright 2002, Elsevier Science (USA). All rights reserved.