Reoperative parathyroid surgery: The importance of ectopic location and multigland disease

Background: Despite the availability of expert surgeons and preoperative imaging investigations, some patients require reoperation for persistent or recurrent hyperparathyroidisms. Method: Fifty consecutive patients were reviewed. Results: There were 28 persistent cases (24 primary, 4 secondary) and 22 recurrent cases (15 primary, 7 secondary) and 98% had successful surgical treatment. Multigland disease was present in 24 of 39 (62%) of primary cases, 11 of 24 persistent and 13 of 15 recurrent (P < 0.02). Four patients in the recurrent primary group had multiple endocrine neoplasia type 1, whereas the other 20 primary patients had sporadic multigland disease. Multigland disease was present in all secondary cases and was a very important factor in this entire series of patients (70%). Regrowth of a remnant of a gland biopsied or partially resected at an earlier operation was the cause of recurrence in 12 of 15 primary and 2 of 7 secondary cases (P < 0.05). The site of missed glands in persistent disease was ectopic in 60%. Ectopic glands were found in the following sites: intrathyroidal 10 (8 inferior and 2 superior), intrathymic 9, posterior mediastinum 4, base of skull 2, carotid sheath 1 and supernumerary 5. Investigations to locate missing glands were positive in 28 of 43 sestamibi scans (65%), 14 of 34 ultrasound scans (41%), 10 of 24 computed tomography scans (42%) and 11 of 13 selective venous sampling tests (85%). Conclusion: Some persistent cases are unavoidable because of ectopic locations and some recurrences are inevitable because of multigland disease.

Conditional inactivation of the Men1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues

Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1(-/-) genotype and leads to beta-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause beta-cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor ( CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing

Introduction: Mutation testing for the MEN1 gene is a useful method to diagnose and predict individuals who either have or will develop multiple endocrine neoplasia type 1 ( MEN 1). Clinical selection criteria to identify patients who should be tested are needed, as mutation analysis is costly and time consuming. This study is a report of an Australian national mutation testing service for the MEN1 gene from referred patients with classical MEN 1 and various MEN 1- like conditions. Results: All 55 MEN1 mutation positive patients had a family history of hyperparathyroidism, had hyperparathyroidism with one other MEN1 related tumour, or had hyperparathyroidism with multiglandular hyperplasia at a young age. We found 42 separate mutations and six recurring mutations from unrelated families, and evidence for a founder effect in five families with the same mutation. Discussion: Our results indicate that mutations in genes other than MEN1 may cause familial isolated hyperparathyroidism and familial isolated pituitary tumours. Conclusions: We therefore suggest that routine germline MEN1 mutation testing of all cases of classical'' MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services. We do not recommend routine sequencing of the promoter region between nucleotides 1234 and 1758 ( Genbank accession no. U93237) as we could not detect any sequence variations within this region in any familial or sporadic cases of MEN1 related conditions lacking a MEN1 mutation. We also suggest that testing be considered for patients < 30 years old with sporadic hyperparathyroidism and multigland hyperplasia

Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-induced bone loss in adult mice

Reduction in levels of sex hormones at menopause in women is associated with two common, major outcomes, the accumulation of white adipose tissue, and the progressive loss of bone because of excess osteoclastic bone resorption exceeding osteoblastic bone formation. Current antiresorptive therapies can reduce osteoclastic activity but have only limited capacity to stimulate osteoblastic bone formation and restore lost skeletal mass. Likewise, the availability of effective pharmacological weight loss treatments is currently limited. Here we demonstrate that conditional deletion of hypothalamic neuropeptide Y2 receptors can prevent ongoing bone loss in sex hormone-deficient adult male and female mice. This benefit is attributable solely to activation of an anabolic osteoblastic bone formation response that counterbalances persistent elevation of bone resorption, suggesting the Y2-mediated anabolic pathway to be independent of sex hormones. Furthermore, the increase in fat mass that typically occurs after ovariectomy is prevented by germ line deletion of Y2 receptors, whereas in male mice body weight and fat mass were consistently lower than wild-type regardless of sex hormone status. Therefore, this study indicates a role for Y2 receptors in the accumulation of adipose tissue in the hypogonadal state and demonstrates that hypothalamic Y2 receptors constitutively restrain osteoblastic activity even in the absence of sex hormones. The increase in bone formation after release of this tonic inhibition suggests a promising new avenue for osteoporosis treatment.

New era: Prophylactic surgery for patients with multiple endocrine neoplasia-2A

Background: The surgical management of patients with multiple endocrine neoplasia-2A (MEN-2A) continues to evolve with specific genotype-phenotype correlations allowing for a more tailored approach. In this study, we report the surgical management of one of the largest MEN-2A families with a rearranged during transfection (RET) codon 804 mutation. Method: This is a cohort study comprising all at-risk kindred within a single known MEN-2A family. Prophylactic total thyroidectomy with lymph node dissection was recommended to all mutation carriers aged 5 years and older. Results: There were a total of 48 at-risk individuals in the MEN-2A kindred, with 22 patients undergoing thyroidectomy after appropriate preoperative evaluation. A total of 9 patients had medullary thyroid cancer including 5 with a normal preoperative calcitonin level. A total of 11 patients had C-cell hyperplasia and 7 showed histological evidence of parathyroid disease. Only the index case had a phaeochromocytoma. Conclusion: Genetic testing for germline mutations in the RET proto-oncogene has allowed precise identification of affected RET carriers and provided the opportunity for prophylactic or 'preclinical' surgery to treat and in fact to prevent medullary thyroid cancer. This concept of prophylactic surgery based on a genetic test is likely to be applied more widely as the tools of molecular biology advance.

With the best of intentions: Is it possible to meet the CARI guidelines?

The CARI1 draft dialysis guidelines propose evidence based targets for biochemical and haematological parameters in ESRF. As part of a prospective randomised trial we investigated our ability to apply the CARI and National Heart Foundation of Australia targets to a representative dialysis population. All patients aged between 18–80 yrs were encouraged to enroll regardless of prior history of non-compliance or co-morbidity. Patients were randomised to either usual care (U;n = 44) or focussed care (F;n = 45). Usual care involved monthly blood tests and pysician review second monthly. In addition focus care patients had a monthly review in a physician supervised trial clinic run by nurses. The groups were comparable at baseline in terms of age, gender, dialysis modality, proportion of diabetics, time on dialysis, haemoglobin, ferritin, % saturation, parathyroid hormone, serum corrected calcium, serum phosphate, total cholesterol and LDL. At 6 months there had been significant improvements in PTH (p < 0.05), total cholesterol (p < 0.05) and LDL (p < 0.001), and a trend to better BP control. The proportion of patients meeting targets at 6 months were as follows: tot chol < 5 mmol/l-U 63%, F 82%; LDL < 3 mmol/l-U 75%, F 91%; phosphate < 1.8 mmol/l- U 42%, F 62%; PTH < 21 pmol/l-U 21%, F 40%; BP sys < 140 mmHg-U 41% F 46%; Hb > 11.5 g/dl U 58% F 64%. In spite of an intensive programme to maximise management of the haematological and biochemical parameters in patients with ESRF it appears that in a significant proportion of patients these targets could not be reached. 1The CARI Guidelines (Caring for Australians with Renal Impairment). Australian Kidney Foundation & Australia New Zealand Society of Nephrology, 2001.