Faculty Bibliography

Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P < 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies.

Terminal deletions on the X chromosome in female patients may be detected as part of a work up for infertility, premature ovarian insufficiency (POI) or in screening for fragile X carrier status. We present the clinical, cytogenetic and molecular features of four patients with terminal deletions of chromosome X that include the FMR1 gene, and discuss biological and genetic implications of this deletion. Providers should be aware of possible identification of Xq27 deletions as a potential outcome of fragile X screening.

BACKGROUND: Over the last few years, major health care systems have been trying to control increasing pharmaceutical expenditures by a variety of methods, such as the controversial copayment policy, as essential health expenditures were being jeopardized. OBJECTIVE: To analyze the regulatory intervention of preauthorization on a rofecoxib model in the medical corps of the Israeli Defense Forces (IDF) in terms of indications for prescription, consumption, and cost. INTERVENTIONS: Guidelines established by the medical services branch based on current literature and communication with diverse specialists and hospitals were implemented by a general practitioner who checked each rofecoxib prescription that was written for IDF personnel by a specialist. The intervention was initiated in November 2000 and continued until August 2001 and after the study. DESIGN: The study was divided into two parts. The first part was a retrospective monthly, preintervention analysis of computerized medical records of IDF personnel (N = 247) for whom rofecoxib was prescribed. The second was a prospective monthly, postintervention analysis of filled-out guideline forms (N = 250) of approved rofecoxib prescriptions. PARTICIPANTS: Patients, were IDF personnel, age 18 to 45, treated in military and civilian outpatient clinics for whom rofecoxib was prescribed. SETTING: The study took place at the Medical Service Branch of the IDF between August 2000 and August 2001. RESULTS: We demonstrated a significant decrease in average monthly consumption (43.0%) and estimated monthly expenditures (40.84%) of rofecoxib, as well as significant shifts (p < 0.001) in indications for whom rofecoxib was approved. These shifts (from pre- to postintervention) include the following: others/nonspecified (80 to 12%), known peptic disorder (7 to 32%), peptic complaints (4 to 22%), and rheumatic (8 to 19%). CONCLUSION: This type of intervention can be cost-effective, can provide quality care, and may be a viable alternative to the controversial and problematic copayment policy.