Osteitis fibrosa cystica with renal parathyroid hormone resistance: a review of pseudohypoparathyroidism with insight into calcium homeostasis.

Pseudohypoparathyroidism is a group of diseases characterized by renal resistance to parathyroid hormone. The patients typically have the bony manifestations of hyperparathyroidism, while being hypocalcemic. Pseudohypoparathyroidism has further been subdivided into types Ia, Ib, Ic, and II. Mutations involving any number of domains of the parathyroid hormone receptor, adenylate cyclase, or G proteins may alter the cellular response to parathyroid hormone. This wide range of possible sites of mutation may explain the heterogeneous biochemical, skeletal, and physical phenotypes associated with the various types of pseudohypoparathyroidism. We describe a patient with pseudohypoparathyroidism who was successfully treated with total parathyroidectomy and gland autotransplantation. The complexities of parathyroid hormone cellular interactions and calcium homeostasis are discussed. Pseudohypoparathroidism is an unusual disease; however, it provides an elegant model for studying problems of calcium balance.

Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13.

Multiple endocrine neoplasia type 1 syndrome (MEN1, MIM 131100), an autosomal dominant disease, is characterized by parathyroid hyperplasia, pancreatic endocrine tumors, and pituitary adenomas. These tumors also occur sporadically. Both the familial (MEN1) and the sporadic tumors reveal loss of heterozygosity (LOH) for chromosome band 11q13 sequences. Based on prior linkage and LOH analyses, the MEN1 gene was localized between PYGM and D11S460. Recently, the MEN1 gene (menin) has been cloned from sequences 30-kb distal to PYGM. We performed deletion mapping on 25 endocrine tumors (5 MEN1 and 20 sporadic) by using 21 polymorphic markers on chromosome band 11q13. Of these, two (137C7A, 137C7B) were derived from PYGM-containing BAC (bacterial artificial chromosome-137C7) sequences, one from INT2-containing cosmid sequences and the marker D11S4748, a (CA)20 repeat marker that was developed by us. The LOH analysis shows that the markers close to the MEN1 (menin) gene were not deleted in three of the tumors. These tumors, however, showed LOH for distal markers. Thus, the data suggest the existence of a second tumor suppressor gene on chromosome band 11q13.

The laparoscopic approach for repair of Morgagni hernias.

BACKGROUND AND OBJECTIVES: Morgagni hernias are unusual congenital diaphragmatic hernias that are generally asymptomatic and discovered incidentally. Surgical treatment is indicated once the diagnosis is made. These hernias have traditionally been repaired by the open abdominal or thoracic approaches. We report a case of Morgagni hernia repaired successfully via the laparoscopic approach. METHODS AND RESULTS: The patient was noted to have a large anteromedial diaphragmatic hernia by chest radiograph and CT imaging. He underwent laparoscopy, during which the hernia was reduced and the defect repaired with mesh placement. We used intracorporeal suture placement to anchor the mesh. The patient recovered uneventfully after a short hospitalization. CONCLUSIONS: The laparoscopic approach for repair of Morgagni hernias offers diagnostic advantages as well as the potential for reduced morbidity when compared to laparotomy. We report intracorporeal knot-tying for fixation of the mesh to be a secure and satisfactory means to achieve the laparoscopic repair.

Pancreatic endocrine tumors with loss of heterozygosity at the multiple endocrine neoplasia type I locus.

BACKGROUND: Loss of heterozygosity (LOH) at chromosome 11q13 has been demonstrated in multiple endocrine neoplasia type I (MEN I) and sporadic parathyroid tumors, pituitary adenomas, and a few types of pancreatic endocrine tumors. Gastrinomas are the most common pancreatic endocrine tumor in MEN I. We hypothesized that all pancreatic endocrine tumors have LOH at 11q13, resulting in inactivation of the previously described tumor suppressor gene in this region. METHODS: We analyzed a sporadic gastrinoma, a MEN I-associated gastrinoma, and a nonfunctional pancreatic endocrine tumor from a patient with Von Hippel-Lindau (VHL) disease for LOH at seven loci at 11q13: D11S149, PYGM, D11S427, D11S546, SEA, D11S97, and D11S146. RESULTS AND CONCLUSIONS: We found LOH at 11q13 in all three tumors. The MEN I-associated gastrinoma we analyzed is the first tumor of this type to have LOH. This is also the first report of LOH at 11q13 in a pancreatic endocrine tumor from a patient with VHL. These findings suggest that the etiology of pancreatic endocrine tumor formation involves a common genetic pathway for sporadic, MEN I, and VHL tumors.

Putative tumor-suppressor gene on chromosome 11 is important in sporadic endocrine tumor formation.

Endocrine tumors arising sporadically or as a manifestation of the multiple endocrine neoplasia type I syndrome (MEN I) have been shown to have mutations on chromosome 11. These mutations can be detected at the molecular level by loss of heterozygosity (LOH) for DNA markers from chromosome 11. This study represents one of the largest collections of sporadic endocrine tumors in which LOH was systematically assessed on chromosome 11 for the loci flanking the proposed MEN I region. DNA was isolated from 39 endocrine tumors and probed with 7 DNA probes spanning the region of chromosome 11q13 from the loci PYGM to INT-2. Eleven tumors demonstrated LOH at any two loci in this region. The remaining 28 tumors showed no LOH or were noninformative at these loci. Thus, nearly 30% of these tumors showed LOH in the region (from PYGM to INT-2) that is thought to contain the MEN I gene(s). Previous studies of sporadic endocrine tumors have suggested that these tumors may arise via the same mechanism as tumors of the MEN I syndrome. Namely, these sporadic tumors are thought to result from mutations leading to genetic loss on the long arm of chromosome 11, thereby inactivating a possible tumor-suppressor gene (or genes). These findings strongly support the hypothesis that sporadic pancreatic endocrine tumors share a similar etiology of tumorigenesis with tumors of the MEN I syndrome, which principally involves deletion of a tumor-suppressor element (or elements).

Candida sepsis in surgical patients.

Candidemia in critically ill patients is a significant source of mortality. To identify perioperative risk factors accounting for patient death, we performed a retrospective study of 46 surgical patients with fungemia during the period from 1981 to 1990. Twenty patients survived (43%), and 26 died (57%). Mortality was associated with age older than 46 (p < 0.02, unpaired Student's t-test) and concomitant renal failure, hepatic failure, postoperative shock, or adult respiratory distress syndrome (p < 0.0001, p < 0.0001, and p < 0.05, respectively, chi 2 test). Survival was not influenced by the presence of diabetes, chronic obstructive pulmonary disease, gastrointestinal hemorrhage, pneumonia, alcohol consumption, steroid use, or enteral/parental nutrition. Bacterial speticemia developed in 26 patients (11 lived, 15 died) and typically preceded or was concomitant with the onset of fungal sepsis (88%). Candida albicans was the fungal species most commonly isolated from blood cultures (30 of 46). Its was cultured from other sites in addition to blood in 30 patients. Candidemia carries a higher risk of mortality in older patients and in those with multiple organ dysfunction. Other immunocompromised conditions such as diabetes and steroid use did not increase mortality. These findings suggest that the pathogenicity of Candida sepsis is not solely related to opportunistic superinfections but may reflect failure of other host defense mechanisms. Moreover, the frequent occurrence of bacterial septicemia prior to the development of Candida sepsis further emphasizes the importance of fungal surveillance cultures to detect early fungal colonization in the critically ill.