Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: comparison with sporadic parathyroid adenomas.

A prospective study on the natural course of primary hyperparathyroidism has recently been reported. Since hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is genetically distinct from most forms of sporadic hyperparathyroidism, it is important to know the natural course of hyperparathyroidism in MEN 1 for better clinical management. For this purpose, we retrospectively reviewed clinical parameters of patients with MEN 1 when they were diagnosed as having hyperparathyroidism, and compared them with those of patients with sporadic primary hyperparathyroidism. In patients with MEN 1: 1) levels of intact PTH (i-PTH) gradually increased with age, which accelerated over 40 years; 2) compared to the steep rise in i-PTH levels in aged patients, increase in serum calcium or decrease of serum inorganic phosphate concentration was relatively mild, and 3) the high concentrations of i-PTH in aged patients were not due to renal insufficiency. These features were not observed in patients with sporadic primary parathyroid adenomas. Clinical features of untreated hyperparathyroidism in MEN 1 may be significantly affected by the age of the patient. The effect, if any, of age-dependent deterioration on recurrence rate after subtotal or total parathyroidectomy requires further elucidation.

Enhanced sensitivity to alkylating agent in lymphocytes from patients with multiple endocrine neoplasia type 1.

Chromosome instability is known to be associated with certain autosomal recessive cancer-prone disorders such as Fanconi's anemia. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disorder characterized by development of tumors in two or more endocrine organs, and chromosome instability in patients with MEN 1 has been described. The clinical features of MEN 1 are, however, distinct from other DNA instability syndromes except predisposition to tumors. Therefore, we reevaluated chromosome instability in patients with familial MEN 1. An increase in the frequency of chromosome aberrations was observed in MEN 1 patients but not in control subjects when peripheral mononuclear cells were exposed to an alkylating agent, diepoxybutane (DEB). DEB reduced survival of mononuclear cells in a dose-dependent manner in both MEN 1 patients and control subjects, but this effect was more prominent in MEN I patients. There was no apparent correlation between certain MEN1 gene mutations and sensitivity to DEB. From these results, we conclude that hypersensitivity to alkylating agents exists in patients with MEN 1. Molecular mechanisms of this phenomenon and relationship to tumorigenesis in endocrine organs should be elucidated.

Isolation of iso-grayanotoxin II from leaves of Leucothoe grayana Max. Its X-ray crystallographic analysis and acute toxicity in mice.

The structure of iso-grayanotoxin II, a new diterpenoid from Leucothoe grayana MAX., has been determined as 3 beta,5 beta,6 beta,14 beta,16 alpha-pentahydroxygrayanotox-9(10)-ene by spectroscopic and X-ray crystallographic analysis. The lethal dosage level of iso-grayanotoxin II in mice was lower than that of grayanotoxin III.

Chromogranin A expression in hepatocellular carcinoma in a patient with germline MEN1 gene mutation.

Hepatocellular carcinoma (HCC) was found in a patient with multiple endocrine neoplasia type 1 (MEN 1). The intriguing finding was that the HCC in the patient was positively stained for chromogranin A (CgA), a cellular marker for endocrine and neuroendocrine tumors. The patient had a pancreas endocrine tumor and type C hepatitis, that made pathological diagnosis of the origin of the tumor complicated.

Expression of prolactin-releasing peptide and its receptor messenger ribonucleic acid in normal human pituitary and pituitary adenomas.

The recently identified PRL-releasing peptide (PrRP) is the first hypothalamic peptide hormone that specifically stimulates PRL production from the pituitary gland. Similar to other hypothalamic regulatory hormones, it acts through its specific seven-transmembrane domain, G protein-coupled receptor. Using RT-PCR, we examined messenger ribonucleic acid (mRNA) expression of PrRP and its receptor in normal human pituitary tissue and in pituitary tumors. PrRP mRNA was expressed in all five normal pituitary glands examined. In contrast, PrRP mRNA was detected in only 5 of 11 of the human prolactinomas. All 5 prolactinomas expressing PrRP were responsive to dopamine agonist treatment, whereas PrRP-negative prolactinomas were non- or partially responsive. PrRP mRNA was also detected in 6 of 13 GH-secreting tumors and 5 of 10 clinically nonfunctioning tumors investigated. PrRP receptor mRNA was found in all the normal and neoplastic human pituitary samples studied. The production of PrRP and its receptor by normal and neoplastic pituitary tissue raises the question of whether it may regulate PRL production in an autocrine/paracrine manner in pituitary tissue. Further investigation of PrRP and its receptor expression and function will be needed to clarify its potential role in regulating PRL secretion in normal human lactotrophs and pituitary tumors.

Multiple endocrine neoplasia type 1 concomitant with Prader-Willi syndrome: case report and genetic diagnosis.

A case of multiple endocrine neoplasia type 1 (MEN 1) accompanied with Prader-Willi syndrome (PWS) was reported. Diagnosis of both diseases have been genetically confirmed. Delay in the diagnosis and management for PWS made surgery for endocrine tumors difficult. This is the first report on the concomitance of MEN 1 with PWS.

Autosomally transmitted low concentration of thyroxine-binding globulin.

The gene coding for thyroxine-binding globulin (TBG) is located on the long arm of the X chromosome; thus anomalies of TBG are transmitted in an X-linked fashion. We report a family with decreased concentration of circulating TBG and an unusual pattern of inheritance. In this family, a number of members showed decreased levels of serum TBG. The unusual finding was that the low TBG was transmitted from the male proband to his son. Thyroxine (T4) binding affinity and heat lability of serum TBG of the proband was not different from values obtained from a normal control. All exons and the critical region in the upstream of the TBG gene were sequenced and no alterations were found. The mechanism that causes decreased concentration of TBG of the proband and family members is unknown, but an abnormality in transcription factors that are important for TBG gene expression might be considered.

Premature centromere division in patients with multiple endocrine neoplasia type 1.

Frequency of mitoses with premature centromere division (PCD) was examined in lymphocytes from subjects with multiple endocrine neoplasia type 1 (MEN 1). An increase in PCD after exposure to an alkylating agent was observed in subjects with MEN 1 who carry a heterozygous MEN1 gene mutation but not in normal controls or in affected subjects without the MEN1 gene mutation. These findings support the inclusion of MEN 1 as a chromosome instability syndrome and recognition of PCD as a manifestation of chromosome instability. Furthermore, these results suggest that the MEN1 gene product may function to maintain the integrity of DNA.

Preexisting membranous nephropathy in allograft kidney.

A case of membranous nephropathy, preexisting in a donor kidney, will be reported. A 41-year-old man underwent a cadaver renal transplantation. An allograft biopsy specimen obtained during the operation showed spike formation on periodic acid-silver methenamine staining and deposition of IgG along the glomerular capillary loop on immunoperoxidase staining. Immunofluorescence staining for IgG remained in the specimens obtained on day 11 and after 4 weeks, but markedly decreased in the specimen obtained 7 weeks after transplantation. Electron-dense deposits also decreased in amount, but irregular thickening of the glomerular basement membrane with spikes, electron-lucent washout lesions, and small amounts of electron-dense deposits remained 20 months after the transplantation. These findings suggest that membranous nephropathy, as well as IgA nephritis and diabetic nephropathy, resolve after renal transplantation and that deposition of IgG markedly decreases within a few months after transplantation, but that complete histological restoration of the basement membrane needs at least a few years.

Pheochromocytoma arising from an accessory adrenal gland in a patient with multiple endocrine neoplasia type 2A: transient development of clinical manifestations after hemorrhagic necrosis.

A case of pheochromocytoma arising from an accessory adrenal gland in a patient with multiple endocrine neoplasia type 2A (MEN 2A) is reported. This tumor resulted in autonecrosis which caused transient expression of clinical symptoms. Scintigraphy of the abdomen identified the existence of an additional accessory adrenal gland because of which the patient did not require a supplement of hydrocortisone after bilateral total adrenalectomy. Pheochromocytoma arising from an accessory adrenal gland is rarely reported, and spontaneous remission of clinical symptoms due to necrosis of the pheochromocytoma without a clinical emergency is also unusual. Accessory adrenal glands can be the cellular basis for pheochromocytoma, and the importance of continual follow up for pheochromocytoma in subjects with MEN 2A should be emphasized.

Novel MEN1 gene mutations in familial multiple endocrine neoplasia type 1.

The recent isolation of the gene responsible for multiple endocrine neoplasia type 1 (MEN 1) has enabled direct genetic diagnosis for people with endocrine tumors and family members of affected patients. Although MEN 1 is rarely recognized in the Japanese population compared to its prevalence in Caucasians, we have previously reported a high prevalence of this disease in a limited area (Nagano Prefecture; population, 2.15 million). In this communication, we report mutations of the MEN1 gene in kindreds living in Nagano Prefecture. The absence of a common mutation among these kindreds indicates that the high prevalence of MEN 1 in this area is not due to a regional accumulation of patients descended from a common ancestor. This result implies that the prevalence of MEN 1 in other areas of Japan could also be higher than had been thought.

Hyperfunctioning thyroid adenoma concomitant with papillary thyroid carcinoma, follicular thyroid adenoma and primary hyperparathyroidism.

A case of 67-year-old woman with hyperthyroidism due to functioning thyroid adenoma is reported. The patient had concomitant follicular thyroid adenoma and primary hyperparathyroidism in addition to functioning adenoma. Histological examination of the excised thyroid tissue revealed occult papillary carcinoma within a functioning adenoma. Genetic analysis of such tumors indicated that functioning adenoma and papillary carcinoma may be etiologically independent. There have been a number of case reports on the coexistence of functioning thyroid adenoma and thyroid cancer or hyperparathyroidism, but none of the studies had examined the etiologic relationship of these lesions on a genetic basis. Furthermore, to our knowledge, this is the first report of the concurrence of four tumors in the neck, functioning thyroid adenoma, papillary thyroid carcinoma, follicular thyroid adenoma and parathyroid adenoma.

Ligand- and nuclear factor-dependent change in hydrophobicity of thyroid hormone beta1 receptor.

An aqueous two-phase partitioning assay was performed using in vitro translated human thyroid hormone beta1 receptor (TRbeta1). Wild-type TRbeta1 was less hydrophobic in the presence of both triiodothyronine (T3) and nuclear extract. This reflects a conformational change, or change in electrostatic properties, of the TRbeta1-nuclear factor complex as a result of T3 binding. Mutant TRbeta1s with reduced T3 binding affinity required a higher concentration of T3 for the shift of hydrophobicity, and a mutant without T3 binding activity did not show any shift, even in the presence of 1 mM T3. The unique mutant receptor, R243Q, has impaired transcriptional function despite virtually normal binding affinity for T3. When this mutant was examined in this assay, the shift of hydrophobicity was significantly impaired even in the presence of both nuclear extract and a high concentration of T3. Nuclear extract of COS1 cells did not affect the T3-binding affinity of R243Q. These results indicate that the R243Q mutant has impaired a ligand-dependent conformational change and interaction with nuclear factor(s). Inability of R243Q to interact normally with nuclear factor(s) may explain, in part, the molecular mechanism of discordance between ligand binding and transactivation function of this mutant.

Sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a kidney transplant recipient.

A case of sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a cadaver renal transplant recipient is reported in this article. The patient underwent a kidney transplant at the age of 43 and was treated with various immunosuppressive agents after surgery. Twelve months after the transplantation, multiple tumors were found in the liver, and the patient died 8 months later. Pathological examination at autopsy revealed renal cell carcinoma with a sarcomatoid component in the right native kidney and metastases to liver and bones. It is unusual for renal cell carcinoma to undergo sarcomatous transformation and to metastasize to the liver before reaching other organs. We speculate that immunosuppressants may have altered malignant cell proliferation, invasion, and the form of metastasis in this case.

Multiple endocrine neoplasia type 1 is not rare in Japan.

Multiple endocrine neoplasia type 1 (MEN 1) is rarely reported in Japanese and other oriental populations. To examine if there is a racial difference in the prevalence of MEN 1, we initiated extensive work on patients with endocrine tumors for additional lesions, and annual screening of family members of affected patients. In a four-year study, eleven asymptomatic patients were found by family screening, and the number of patients with MEN 1 in our clinics increased from 16 to 38. Estimated prevalence of MEN 1 was no less than 0.018/1000. MEN 1 may not be as rare as had been thought in Japanese, and the prevalence of MEN 1 in Japanese would not be significantly different from that of Caucasians. Systemic surveillance and extensive screening of family members are required for early detection and management of patients.

Genetic screening in hereditary multiple endocrine neoplasia type 1: absence of a founder effect among Japanese families.

Ten Japanese families with hereditary multiple endocrine neoplasia type 1 (MEN1) were examined. Five DNA polymorphic markers on the long arm of chromosome 11 were analyzed for genetic screening of MEN1 in members of affected families, and disease carriers were identified before clinical manifestations. Unlike MEN1 families in Newfoundland or in Tasmania, no consistent haplotypes were segregated with the disease in the Japanese families when defined by 5 nearby markers. The identification of asymptomatic disease carriers is of substantial clinical importance for early management, genetic counseling and to avoid unnecessary screening for non-disease carriers. However, genetic screening of family members by polymorphic markers could be useful only to each family, and no generally applicable markers were found for Japanese subjects with MEN1.

Gs alpha mutation may be uncommon in patients with multiple endocrine neoplasia type 1.

Activating mutations of the Gs alpha gene, termed gsp, have been identified in various endocrine tumors. Recently, a high frequency of gsp mutation in patients with multiple endocrinopathies was reported, and a family with both McCune-Albright syndrome and multiple endocrine neoplasia type 1 was described. Each suggests that the oncogenic mutations of Gs alpha may play an important role in tumorigenesis in patients with multiple neoplastic endocrinopathies, and a search for the gsp mutation in multiple endocrine neoplasia type 1 (MEN1) should be undertaken. We, therefore, reevaluated the frequency of gsp mutations in endocrine tumors of patients with MEN1. Of 18 tumors from 13 patients with MEN1, we found no gsp mutations regardless of heredity. We conclude that the gsp mutation may be uncommon in endocrine tumors of MEN1 patients, and thus, this mutation plays little, if any, role in their tumorigenesis.

Transcriptional regulation of human thyroid hormone receptor beta 1 gene expression: effect of human retinoid X receptor and identification of a transcriptional silencer region.

Effects of human retinoid X receptor alpha (hRXR alpha) and its ligand, 9-cis-retinoic acid, on T3-mediated auto-regulation of hTR beta 1 gene expression were examined using a chloramphenicol acetyltransferase (CAT) reporter system, and a deletional analysis of the promoter. hRXR alpha enhanced T3-dependent CAT induction mediated through the proximal (p) TRE in a ligand (9-cis-retinoic acid) independent manner. In a gel mobility shift assay, hRXR alpha enhanced the binding of hTR beta 1 to the pTRE by the formation of hRXR alpha-hTR beta 1 heterodimers. On the other hand, hRXR alpha and 9-cis-retinoic acid did not show any effects on T3-dependent CAT induction mediated through the distal (d) TRE or the binding of hTR beta 1 to the dTRE. A four hundred-base pair (bp) fragment adjacent upstream of the dTRE showed a T3 independent suppressor effect on the function of the pTRE and dTRE. Thus, this region may be an important regulator of the T3 dependent up-regulation of the TR beta 1 gene expression which is observed only under specific conditions.

Response of hepatic proteins to 3,5,3'-tri-iodo-L-thyronine in diabetic rats.

In order to study whether peripheral action of thyroid hormones is altered in insulin deficiency and to elucidate the biological consequences of alteration of the cytosolic 3,5,3'-tri-iodo-L-thyronine (T3) binding protein (CTBP), we measured malic enzyme, T3-responsive nuclear n protein, CTBP and nuclear thyroid hormone receptor in the liver and kidney of streptozotocin (STZ)-induced diabetic rats that were treated with or without insulin and/or a receptor-saturating dose of T3. The following results were obtained. 1. Induction of malic enzyme by T3 was apparently diminished in diabetic rats. However, supplementary injection of insulin enabled previously given T3 to take effect in diabetic rats. 2. T3-responsiveness of other hepatic proteins (n protein and CTBP) was not altered by insulin in diabetic rats. 3. The level of n protein was increased by insulin in diabetic rats in vivo and in perfused rat liver, indicating that the hepatic n protein is a novel insulin-responsive protein. T3 and insulin increased the level of n protein non-synergistically in diabetic rat liver. 4. Hepatic nuclear receptor levels were not altered in diabetic rats. 5. Hepatic CTBP levels were decreased in diabetic rats. This was not due to the toxic effect of STZ. Low CTBP level was only partially increased by insulin after 30 days of diabetic period. Renal CTBP levels were not altered in diabetic rats with or without insulin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired amegakaryocytic thrombocytopenic purpura with humoral inhibitory factor for megakaryocyte colony formation.

A 67-year-old man with thrombocytopenia, and amegakaryocytic but otherwise normal bone marrow, was evaluated. Antibody against thrombocytes was negative and the half-life of thrombocytes was normal. In vitro clonal culture of the patient's bone marrow cells yielded no megakaryocyte colony with normal granulocyte-macrophage and erythroid colony formation. Megakaryocyte colony formation of the control bone marrow cells was significantly suppressed by the addition of the patient's serum to the culture, suggesting the existence of humoral inhibitory factor(s) for megakaryocyte colony formation. Therapeutic trials with plasma exchange, cyclosporine, prednisolone, and cyclosporine plus prednisolone were all unsuccessful, but serious bleeding has been absent.