Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.

Objective: Familial isolated primary hyperparathyroidism (FIHP) is de®ned as hereditary primary hyperparathyroidism without the association of other diseases or tumors. Linkage analyses suggest that different genotypes can lead to the same phenotype of primary hyperparathyroidism. Hereditary syndromes associated with primary hyperparathyroidism are multiple endocrine neoplasia type 1 and type 2 (MEN 1 and MEN 2). In MEN 1, multiple parathyroid adenomas occur in more than 90% of the patients. Therefore, it has been suggested that FIHP could represent a variant or partial expression of MEN 1. Design: We report on a large FIHP kindred with a MEN1 gene mutation. Nineteen family members (aged 10 to 87 years) were screened. Furthermore, statistical comparison by Fisher's exact tests of FIHP families with MEN1 gene mutations and MEN 1 families with two or more endocrinopathies was carried out to investigate genotype±phenotype correlations. Methods: Mutational analysis of leucocyte DNA was carried out by direct sequencing of the complete coding region of the MEN1 gene. Screening of MEN 1 manifestations was carried out by determination of serum calcium, phosphate, parathyroid hormone, prolactin, ACTH, cortisol, IGF-I, gastrin, glucose, insulin, glucagon, serum potassium, aldosterone, plasma renin and urinary hydroxyindoleacetic acid. Results: We detected an in-frame deletion mutation in exon 8 of the MEN1 gene resulting in the deletion of one glutamine acid residue at position 363. It was found in eight individuals. Two of these family members (aged 42 and 60 years) were operated for primary hyperparathyroidism, and three (aged 13 to 40 years) showed mild hypercalcemia and parathyroid hormone levels within the upper normal range or slightly elevated, without any clinical symptoms. Two individuals (aged 12 and 19 years) were normocalcemic. One could not be tested. None of them had clinical evidence of other MEN 1 manifestations. Statistical comparison of the mutation types in families with FIHP and families with two or more MEN 1-associated endocrinopathies reported in other studies reveals a signi®cant difference. In families with FIHP, missense/in-frame mutations have been found in 87.5% of cases whereas in families with tumors in various endocrine glands these mutation types occur much less frequently (21±34%, P , 0X05). Conclusions: These studies indicate that FIHP can represent a partial MEN 1 variant and is often caused by missense/in-frame mutations. European Journal of Endocrinology 145 155±160

Objective: Recent studies have shown an in¯uence of the calcium-sensing receptor variant A986S on the serum calcium concentration, suggesting that this genetic variant could be a candidate for various bone and mineral disorders. The intention of this study was therefore to investigate the frequency of the described calcium-sensing receptor variants A986S, R990G and Q1011E in patients with primary hyperparathyroidism to test the hypothesis as to whether these variants represent risk factors for the development of primary hyperparathyroidism. Design: Fifty patients with primary hyperparathyroidism were included in the study. One hundred and two healthy blood donors served as controls. Methods: Detection of the genetic variants A986S, R990G and Q1011E was done by direct sequencing of exon 7 of the calcium-sensing receptor in leucocyte DNA. Results: The heterozygous variant A986S was found in 34% (17 of 50) of the healthy age-and sexmatched controls and 40% (20 of 50) of the patients with primary hyperparathyroidism. This difference was not statistically signi®cant P 0X68X However, in male patients the heterozygous variant A986S was found more frequently (67%, 6 of 9) than in male controls (20%, 2 of 10, P 0X07). The variants R990G and Q1011E were found less frequently (8±20%) in patients and controls without signi®cant differences between the groups. Patients with the heterozygous variant Q1011E had signi®cantly higher serum calcium and parathyroid hormone levels than patients with the wild-type variant P , 0X01X There was no correlation of serum calcium (total and corrected for albumin) with the calcium sensing receptor variant A986S in 102 healthy blood donors P 0X45X Conclusions: The calcium-sensing receptor variants do not, therefore, seem to be major genetic determinants for the development of primary hyperparathyroidism. The variant A986S may possibly represent a risk factor for the development of parathyroid neoplasia in men. Moreover, the presence of the genotype Q1011E might in¯uence the clinical course of the disease. The previously reported signi®cant correlation of serum calcium levels with the genetic variant A986S in healthy subjects could not be con®rmed.

4 patients of two families with congenital persistent hyperthyroidism without detectable autoantibodies are reported. The members of the first family affected by hyperthyroidism, i.e. the mother and her two children, showed a germline mutation, a transition of GCC to GTC in the genomic DNA of the TSH receptor, leading to an exchange of alanine by valine at the position 623. The mother was thyroidectomized at two times because of recurrent nodular goiter. The third child of a healthy second family showed a transition of AGC to AAC leading to an exchange of serine by asparagine at the position 505 of the TSH receptor. The mutation of family 1, as a somatic point mutation leading to autonomous thyroid adenoma, has originally been demonstrated to constitutively activate TSH independent cAMP accumulation. The functional tests of the TSH receptor gen mutation, detected in family 2, are ongoing, but an exchange of serine by arginine at the same position has been shown to lead to constitutively active cAMP accumulation. The cases of congenital hyperthyroidism in the first family lead to a reduction of the birth weight and head circumference and to a neonatal but not fetal tachycardia. Bone age of both children was accelerated by one year. In contrast to that, congenital hyperthyroidism of the second family lead to more marked signs of intrauterine hyperthyroidism. The mother observed marked symptoms of fetal and neonatal hyperthyroidism. The bone age at a chronological age of 6 months was 4-6 years and the neonate showed a mild exophthalmus. We conclude, that congenital hyperthyroidism due to constitutively activating TSH receptor mutations has to be considered, if hyperthyroidism is not transient but persistent, and the parameters of autoimmunity are absent. Constitutively active TSH receptor germline mutations lead to different degrees of congenital hyperthyroidism. In contrast to patients with Graves' disease, more aggressive means of treatment like total thyroidectomy and/or radiation seem to be recommendable in cases with severe hyperthyroidism to control the disease.

SummaryPrimary hyperparathyroidism (pHPT) is a common endocrine disorder that predominantly affects postmenopausal women. It is mostly caused by solitary tumours within the parathyroid glands. Although the pathophysiology of pHPT is still incompletely understood, recent studies provide new clues on the development and cellular growth of tumours within the parathyroids associated with hypersecretion of parathyroid hormone and hypercalcaemia. The natural course of pHPT is rather benign. Nowadays, it has become an oligo-or asymptomatic disease often only detected by routine blood tests. These facts raise the question whether to perform parathyroidectomy on oligo-and asymptomatic patients with pHPT or whether it is possible to monitor these patients without surgery. The aim of this article is to review the literature as regards (i) the pathophysiological mechanisms that underlie parathyroid neoplasia and (ii) the defective calcium-sensing in patients with pHPT (iii) environmental and /or genetic risk factors that predispose to or promote parathyroid neoplasia, as well as (iv) alternative approaches to treat oligo-and asymptomatic patients with pHPT medically.Maintenance of a normal extracellular calcium concentration (2·2-2·6 mmol/l) depends on the integrated co-ordination of calcium fluxes with respect to intestinal tract, kidneys and bone. Changes in extracellular calcium levels are mainly regulated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (reviewed in Bushinsky & Monk, 1998). Secretion of PTH is regulated by extracellular calcium, via a G protein-coupled calcium-sensing receptor (CaR;Brown et al ., 1993). Small increments in extracellular calcium levels above normal inhibit PTH secretion. Subsequently, calcium uptake from intestine, renal reabsorption and release of calcium from bone are reduced to re-establish the normal value (see Fig. 1). If serum calcium concentration falls by only a few per cent, secretion of PTH is stimulated, and calcium uptake from the intestines, release from bone and reabsorption from the kidneys are increased (reviewed in Bushinsky & Krieger, 1992a, 1992b. In part, these effects are mediated by 1,25-dihydroxyvitamin D, whose synthesis is tightly regulated by PTH, as well as by calcium, phosphate and 1,25-dihydroxyvitamin D itself (Kumar, 1984;Breslau, 1988). In patients with primary hyperparathyroidism (pHPT), the normal regulation of PTH secretion is disrupted. In spite of increased levels of total and ionized serum calcium, its biologically active compound, hypersecretion of PTH is observed. In general, measurement of serum calcium and intact PTH (1 -84 amino acids) levels confirm the diagnosis.Newly developed PTH assays, which specifically recognize the biologically active form of the peptide (1 -84), seem to be more sensitive compared to standard immunoassays that also bind to smaller fragments of PTH (Gao et al ., 2001;Nakanishi et al ., 2001). However, these amino-terminally truncated PTH Correspondence: R. Paschke, III. Medical Department, University of Leipzig, ...