Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3.

INTRODUCTION: Array comparative genomic hybridisation (array CGH) is a powerful method that detects alteration of gene copy number with greater resolution and efficiency than traditional methods. However, its ability to detect disease causing duplications in constitutional genomic DNA has not been shown. We developed an array CGH assay for X linked hypopituitarism, which is associated with duplication of Xq26-q27. METHODS: We generated custom BAC/PAC arrays that spanned the 7.3 Mb critical region at Xq26.1-q27.3, and used them to search for duplications in three previously uncharacterised families with X linked hypopituitarism. RESULTS: Validation experiments clearly identified Xq26-q27 duplications that we had previously mapped by fluorescence in situ hybridisation. Array CGH analysis of novel XH families identified three different Xq26-q27 duplications, which together refine the critical region to a 3.9 Mb interval at Xq27.2-q27.3. Expression analysis of six orthologous mouse genes from this region revealed that the transcription factor Sox3 is expressed at 11.5 and 12.5 days after conception in the infundibulum of the developing pituitary and the presumptive hypothalamus. DISCUSSION: Array CGH is a robust and sensitive method for identifying X chromosome duplications. The existence of different, overlapping Xq duplications in five kindreds indicates that X linked hypopituitarism is caused by increased gene dosage. Interestingly, all X linked hypopituitarism duplications contain SOX3. As mutation of this gene in human beings and mice results in hypopituitarism, we hypothesise that increased dosage of Sox3 causes perturbation of pituitary and hypothalamic development and may be the causative mechanism for X linked hypopituitarism.

Parathyroid adenomas and hyperplasia. Dual radionuclide scintigraphy and bone densitometry studies.

Dual radionuclide imaging of the neck (Tc-99m pertechnetate and TI-201 thallous chloride) was performed in 22 patients with chemical evidence of hyperparathyroidism (elevated blood calcium and parathormone [PTH] levels). Of these, 19 of 22 had localization of a TI-201 "excess" area on radiothallium-radiotechnetium subtraction images. In 13 patients who have had operative confirmation at this writing, the dual radionuclide imaging was positive in 12 (12/13 = 92.3%). One patient had two parathyroid adenomas, both of which were seen on the images; thus, overall detection was 13 out of 14 or 92.8%. The parathyroid adenomas visualized weighed from 0.06 to 3.0 g; the one not detected weighed 0.25 g. In three patients with parathyroid hyperplasia secondary to renal disease, the subtraction imaging detected eight of 12 glands (66.7%). The forearm bone mineral content and bone density were determined in eight patients with parathyroid adenomas; results were abnormally low in five of these eight. One of the three patients with secondary hyperparathyroidism had an abnormally low radial bone mass. The combination of dual radionuclide imaging and radial bone mass determination may present a useful approach in both localizing abnormal parathyroid tissue and in examining its functional consequences.

Cushing's syndrome due to ectopic production of corticotropin-releasing factor.

A patient with Cushing's syndrome is described who had a metastatic medullary carcinoma of the thyroid which contained corticotropin-releasing factor. ACTH was found by an immunohistochemical method in the patient's pituitary, but not in the thyroid tumor. This is the second report demonstrating corticotropin-releasing factor in tumor tissue in this syndrome. Wider use of immunohistological methods can help distinguish this variety from other tumors associated with the ectopic ACTH syndrome when bioassays are not available.

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California. Coronary heart disease risk factors in Japan and Hawaii.

Various risk factors were evaluated to explain a significantly greater incidence of coronary heart disease in men of Japanese ancestry resident in Hawaii compared with men resident in Japan. The independent predictors of incidence of coronary heart disease in both Japan and Hawaii were systolic blood pressure, serum cholesterol, relative weight and age. These factors appeared to influence incidence similarly in both areas because in each case the correlation coefficients for Japan and Hawaii did not differ significantly. The hypothesis that the greater incidence in Hawaii could be attributed to differences in levels of these risk factors was tested with the Walker-Duncan method. The four variable multiple logistic function describing the probability of coronary heart disease in Japan was applied to the cohort characteristics observed in Hawaii. The estimated incidence thus obtained was not significantly different from that actually observed in the men resident in Hawaii. Therefore the increased coronary risk profile in Hawaii compared with Japan can account for the greater incidence of coronary heart disease in the former. Current cigarette smoking was significantly related to the risk of coronary heart disease in Hawaii but not in Japan. This difference requires further investigation.

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California. Incidence of myocardial infarction and death from coronary heart disease.

The incidence of myocardial infarction and death from coronary heart disease was studied in defined samples of 45 to 68 year old Japanese men in Japan, Hawaii and California. The incidence rate was lowest in Japan where it was half that observed in Hawaii (P less than 0.01). The youngest men in the sample in Japan were at particularly low risk. The incidence among Japanese men in California was nearly 50 percent greater than that of Japanese in Hawaii (P less than 0.05). A striking increase in the incidence of myocardial infarction appears to have occurred in the Japanese who migrated to the United States; this increase is more pronounced in California than in Hawaii.

Salivary gland neoplasms following atomic radiation: additional cases and reanalysis of combined data in a fixed population, 1957-1970.

A reappraisal was made of the relationship between exposure to atomic radiation in 1945 and the occurrence of salivary gland tumors in heavily exposed survivors. This was made possible by the discovery of 8 additional patients; the total now reported consists of 30 cases. In those exposed to 300+ rads, the number of cases was significantly (p less than .01) greater than expected. This was found for the combined group and for malignant types, but not for histologically benign tumors. Our prior conclusion regarding the high-dose radiation effect upon salivary gland neoplasia remains unchanged in the reanalysis; however, our suggestion that younger persons were at significantly greater risk is weakened.