Luís G. Sobrinho

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

CHARACTERIZATION OF BIG, BIG PROLACTIN IN PATIENTS WITH HYPERPROLACTINAEMIA

OBJECTIVE The present study was designed to characterize the clinical findings of patients with macroprolactin‐aemia (sustained hyperprolactinaemia where the predominant form of prolactin is of large molecular size) and to further assess the bioactivity and structure of big, big prolactin (BB‐PRL).

Searching for RET/PTC rearrangements and BRAF V599E mutation in thyroid aspirates might contribute to establish a preoperative diagnosis of papillary thyroid carcinoma.

Objective:  Searching for multiple molecular markers in thyroid aspirates appears to be a promising approach for establishing a preoperative diagnosis of papillary thyroid carcinoma (PTC).

Mutational Analysis of Portuguese Families with Multiple Endocrine Neoplasia Type 1 Reveals Large Germline Deletions

objective To determine the spectrum of MEN1 mutations in Portuguese kindreds, and identify mutation‐carriers.

Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations.

Linkage analysis has identified four familial non-medullary thyroid carcinoma (FNMTC) susceptibility loci: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32) and TCO (19p13.2). To date, there is no evidence for the involvement of genes from the RAS/RAF signalling pathway in FNMTC. The aim of our study was to evaluate the role of the four susceptibility loci, and RAS/RAF signalling pathway genes, in FNMTC. In total, 8 FNMTC families, and 27 thyroid lesions from family members (22 papillary thyroid carcinomas (PTCs): 11 classic, 10 of the follicular variant and 1 of the mixed variant; 4 follicular thyroid adenomas (FTAs) and 1 nodular goitre (NG)), were evaluated for the involvement of the four susceptibility regions, using linkage and loss of heterozygosity (LOH) analyses. BRAF and H-, N- and K-RAS mutations were also screened in the 27 lesions and patients. Linkage analysis in seven informative families showed no evidence for the involvement of any of the four candidate regions, supporting a genetic heterogeneity for FNMTC. Twenty tumours (74%), of which 18 were PTCs, showed no LOH at the four susceptibility loci. The remaining seven tumours (four PTCs, two FTAs and one NG) showed variable patterns of LOH. Fourteen tumours (52%) had somatic mutations: BRAF-V600E mutation was observed in 9 out of the 22 PTCs (41%); and H-RAS and N-RAS mutations were detected in 5 out of the 22 PTCs (23%). Our data suggest that the four candidate regions are not frequently involved in FNMTC and that the somatic activation of BRAF and RAS plays a role in FNMTC tumourigenesis.

Mapping the Gene Causing Hereditary Primary Hyperparathyroidism in a Portuguese Kindred to Chromosome 1q22-q31

A Portuguese kindred with autosomal dominant isolated primary hyperparathyroidism (HPT) that was associated with parathyroid adenomas and carcinomas was investigated with the aim of determining the chromosomal location of this gene, designated HPTPort. Leukocyte DNA from 9 affected and 16 unaffected members and 7 parathyroid tumors from 4 patients was used in comparative genomic hybridization (CGH), tumor loss of heterozygosity (LOH), and family linkage studies. The CGH studies revealed abnormalities of chromosomes 1 and 13, and the results of LOH studies were consistent with the involvements of tumor suppressor genes from these regions. Family segregation studies mapped HPTPort to chromosome 1q22‐q31 by establishing linkage with eight loci (D1S254, D1S222, D1S202, D1S238, D1S428, D1S2877, D1S422, and D1S412) (peak two‐point LOD scores = 3. 46–5.14 at 0% recombination), and defined the location of HPT Port to a 21 cM region flanked centromerically by D1S215 and telomerically by D1S306. Thus, HPTPort has been mapped to chromosome 1q22‐q31, and a characterization of this gene will help to elucidate further the mechanisms that are involved in the development of parathyroid tumors.

Quality of life is decreased in female patients treated for microprolactinoma

In the August issue of the European Journal Endocrinology, Kars et al. (1) reported that quality of life of female patients treated for microprolactinoma is decreased when compared with that of appropriately chosen controls. These observations were independent of the current values of serum prolactin and of current intake, or not, of dopamine agonists, their composition or dosage. The Authors speculated that the decreased quality of life might depend on the past exposure of the brain or of other tissues to hyperprolactinemia or on the disclosure of the diagnosis of a pituitary tumor. There is a third, alternative, explanation. Life events have been reported to often precede the clinical onset of prolactinomas (2, 3). Also, paternal deprivation early in life has been reported with unusual frequency in women with prolactinomas (2, 4). Both sets of observations indicate that environmental factors may play a role in the clinical expression of prolactinomas. It is, therefore, likely that prolactinomas develop preferentially in women predisposed to activate prolactin secretion in response to some stresses, either because they were primed early in life by paternal deprivation or for some other reasons. These women may also be particularly vulnerable to anxiety and depression. In short, anxiety, depression, and other features of poor quality of life may depend on pre-existent characteristics

A practical method for the detection of macroprolactinaemia using ultrafiltration

objective The aim of this study was to evaluate a method for the estimation of the percentage of big‐big prolactin (bb‐PRL) in serum, based on centrifugal ultrafiltration (UF) and to be used for the detection of macroprolactinaemia.

Expression of iodine metabolism genes in human thyroid tissues: evidence for age and BRAFV600E mutation dependency

Context  Children present a higher susceptibility to developing thyroid cancer after radioiodine exposure and also a higher frequency of functional metastases than adults.

RET polymorphisms and sporadic medullary thyroid carcinoma in a Portuguese population.

The genetic basis of the sporadic form of medullary thyroid carcinoma, derived from “C” cells, is still poorly understood. Somatic mutations of RET proto-oncogene have been reported at a variable frequency ranging from 23% to 69%. The hypothesis that low penetrance factors, such as polymorphisms, might contribute to the phenotype of this neoplasm has been addressed in a few studies conducting to conflicting results. Herein, we studied 100 individuals (50 patients and 50 controls) aiming to compare the frequencies of G691S, L769L, S836S, and S904S RET polymorphisms observed in patients with respect to controls. Furthermore, metaanalysis of published studies including the present results was conducted. To test the contributory role of the above polymorphisms for the development of “C”-cell hyperplasia, we studied a group of 10 individuals selected for having a positive pentagastrin test despite the absence of a RET germline mutation. An over-representation of the G691S polymorphism, particularly in females, was observed in patients with respect to controls, although not reaching the level of significance. Allelic frequencies of the other three polymorphisms were not different in patients and controls. Results obtained in the admittedly small group of individuals with a positive pentagastrin test are unlikely to support a major influence of any polymorphism in the development of “C”-cell hyperplasia. The meta-analysis provided evidence for a significant association of the S691 allele with MTC (odds ratio 1.54, 95% confidence interval 1.12–2.12, p=0.008) and found no significant associations for the other polymorphisms.