Philip E. Harris

A Family with Isolated Hyperparathyroidism Segregating a Missense MEN1 Mutation and Showing Loss of the Wild-Type Alleles in the Parathyroid Tumors

We thank Mr. Ashley Brown and Mr. Hedley Berry for allowing us to study their patients. This study was supported by the Swedish Cancer Foundation and the Gustav Vs Jubilee Fund. B.T.T. is a postdoctoral fellow of the Torsten and Ragnar Soderberg Memory Foundations.

Gsα and Gi2α mutations in clinically non-functioning pituitary tumours

BACKGROUND AND OBJECTIVE Activating mutations of Gsα (gsp) and Gi2α (gip) have been described in various endocrine neoplastic conditions. The objective of this study was to assess the prevalence of gsp and gip mutations in clinically non‐functioning pituitary tumours (NFTs) and to compare the clinical phenotypic characteristics of tumours bearing G protein gene mutations with wild‐type tumours.

Genetic studies of a family with hereditary hyperparathyroidism–jaw tumour syndrome

Familial hyperparathyroidism may occur as familial isolated hyperparathyroidism (FIHP) or as part of an inherited syndrome, in particular multiple endocrine neoplasia types 1 and 2 A (MEN1, MEN2A) and hyperparathyroidism–jaw tumour (HPT–JT) syndrome. The localization of the genes responsible for these syndromes has enabled genetic screening of families with primary hyperparathyroidism (PHPT) to be carried out. This has important clinical implications in terms of individual follow‐up and management. We previously reported a large FIHP family with an increased risk of parathyroid cancer and excluded its linkage to MEN1, MEN2 and PTH genes. Here we re‐analysed this family and performed genetic linkage to the HPT–JT locus in chromosome 1q21‐q32. Loss of heterozygosity studies of 1q21‐q32, 11q13 and X chromosome were also performed.

The Treatment of De Novo Acromegalic Patients with Octreotide-LAR: Efficacy, Tolerability and Cardiovascular Effects

AbstractAim: Somatostatin analogues are normally used as adjunctive therapy to surgery and radiotherapy in management of acromegaly. We studied the effects of de novo OCT-LAR treatment on growth hormone (GH) suppression, tumour size, cardiovascular function, clinical symptoms, signs and quality of life in 9 newly diagnosed acromegalic patients. Methods: Patients commenced OCT-LAR 20 mg IM monthly for 2 months. Dose increased to 30 mg monthly if mean serum GH (MGH) >5 mU/l (2 μg/litre) (7 patients). Treatment continued for 6 months. Cardiac function assessed by echocardiography at baseline and day 169. Left ventricular (LV) mass and ejection fraction (EF) calculated from 2D M-mode studies. Results: Serum GH demonstrated suppression in 8/9 patients (mean suppression 64.9% ± 29.7%, range; 4–95.2%). MGH suppressed <5 mU/l (2 μg/litre) in 3 (33%) patients. IGF-I and IGFBP3 normalised in 1 (12.5%) and 3 (38%) patients respectively. Tumour shrinkage seen in 30% patients. Eight patients were assessed by echocardiography. At baseline, 7 patients demonstrated abnormalities in LV mass and EF. At day 169, 6 patients demonstrated a fall and 1 an increase in LV mass. Overall there was no significant change in LV mass. A significant increase in EF was observed (p = 0.02). There were significant improvements in health perception (p = 0.01), fatigue (p < 0.05) and perspiration (p = 0.0039). Conclusions: These data demonstrate OCT-LAR provides adequate control of acromegaly in a proportion of patients treated over 6 months. This is associated with improved LV function, evidenced by increased EF. Improved results are expected with longer-term treatment. OCT-LAR may be considered as primary treatment for acromegaly in selected patients.

Corticotroph carcinoma presenting as a silent corticotroph adenoma.

Malignant pituitary tumours are rare and their pathogenesis is not fully understood. We have performed genetic analyses on tissues arising from a pituitary carcinoma that initially presented as a silent corticotroph adenoma but which failed to respond to repeated, aggressive surgical and medical therapy. Loss of heterozygosity (LOH) of known or putative tumour suppressor genes (TSG) was assessed by microsatellite analysis of microdissected tumour and matched patient blood DNA. Clonality of the pituitary tumour samples was analysed by two PCR-based techniques; one employing the highly polymorphic short tandem repeat (STR) within the human androgen receptor allele (HUMARA), another based on a restriction fragment length polymorphism of the X chromosome phosphoglycerokinase (PGK-1) gene. Screening with 9 microsatellite markers demonstrated allelic loss at 3 sites (D1S190, D3S1283 and D10S297) in all tumour samples except the presenting pituitary tumour. X chromosome inactivation analysis demonstrated polyclonality in the original presenting tumour and a metastatic deposit but monoclonality in tissue samples from a second and third transsphenoidal resection. In these cases of tumour recurrence both LOH and X chromosome inactivation suggest that monoclonality arose from preferential clonal growth from the original polyclonal tumour. Polyclonality of the metastatic deposit suggests that this was derived from the presenting tumour, although the LOH pattern indicates that a single clone dominates. The data are consistent with increasing allelic loss associated with tumour dedifferentiation and malignant transformation.

Biochemical markers for clinically non-functioning pituitary tumours.

Clinically, non-functioning pituitary adenomas (NFAs) comprise about 30% of pituitary tumours. Unlike other types of pituitary tumour, most NFAs present with pressure symptoms and/or hypopituitarism rather than with clinical syndromes related to hormone hypersecretion. Non-functioning adenomas and gonadotrophinomas are almost certainly derived from the same gonadotroph cell lineage. They form a part of a spectrum of phenotypes, ranging from the truly null cell adenoma to the gonadotrophinoma, which may be associated with elevated (sometimes markedly) serum gonadotrophin levels. The latter tumours are characteristically large and invasive. Occasionally, they may be associated with clinical evidence of gonadotrophin hypersecretion (Heseltineet al., 1989). Nonetheless, the majority of NFAs express mRNA and/or immunostain for glycoprotein hormone subunits (Lloyd et al., 1991). Similarly, a majority will secrete one or more of these subunits in vitro (Asa et al., 1992). There have been a number of reports describing the measurement of intact gonadotrophins and their subunits in patients with NFAs. Gonadotrophinomas secrete intact FSH more commonly than LH (Katznelson et al., 1993) and this may be biologically active (Galwayet al., 1990). More commonly, tumours secrete biologically inactive b-subunits (Daneshdoost et al., 1993; Gil del Alamoet al., 1994; Chansonet al., 1997). There is often associated hypersecretion of glycoprotein hormonea-subunit. A proportion of NFAs secrete a-subunit alone (Katznelsonet al., 1993). Greenmanet al. (1998) describe the study of b-FSH and b-LH secretion by NFAs before and three months following transsphenoidal surgery. Using fluoroimmunoassays, they report that pathological responses of b-LH and b-FSH to TRH were present in 79% and 60% of patients respectively. The study group as a whole did not demonstrate any significant changes inb-subunit levels following surgery. There were, however, quite heterogeneous responses seen at an individual level. Post-operativeb-LH levels and responses to TRH were reduced in the patients with the elevated pre-operative levels. Three patients who had an absence of residual tumour on imaging lost the pathological b-LH responses to TRH postoperatively. Four patients demonstrated a significant decrease in b-LH levels following surgery, but large tumour remnants were still present on post-operative imaging. Conversely, three patients with normal pre-operative b-LH responses developed abnormal responses following surgery. The authors conclude that TRH-inducedb-LH responses in patients with NFAs are too heterogeneous to allow its routine use in the post-operative follow-up of patients. What is the practical relevance of intact gonadotrophin or gonadotrophin subunit secretion by these tumours? As has been mentioned, from the clinical point of view most NFAs are biologically quiescent. Imaging with MRI provides the best guide to their management. The advent of MRI imaging has enabled the clinician to follow patients post-surgery without automatically resorting to radiotherapy as in the past. There is little doubt that, in this context, MRI imaging has represented the greatest advance in the management of NFAs in the last decade. Elevated serum glycoprotein hormone subunit levels can, however, provide useful tumour markers in individual cases. Although the use of such tumour markers alone can be misleading, they provide a useful adjunct to MRI imaging in the follow-up and management of patients with these tumours.