Giovanni Pinna

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

OBJECTIVE Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population. METHODS We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres. RESULTS AND CONCLUSIONS The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001). Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.

Autoimmune hypophysitis of SJL mice: clinical insights from a new animal model.

Autoimmune hypophysitis (AH) is a rare but increasingly recognized disease of the pituitary gland. Its autoantigens are unknown, and the management is difficult because it is often misdiagnosed as a nonsecreting adenoma. By immunizing female SJL/J mice with mouse pituitary extracts, we established a new mouse model of experimental AH. Immunized mice developed severe lymphocytic infiltration in the anterior pituitary that closely mimicked the human pathology. In the early phase of experimental AH, the pituitary enlarged, consistent with the compression symptoms reported by hypophysitis patients at presentation. In the florid phase, adrenal insufficiency and pituitary antibodies developed, in strong correlation with the pituitary pathology. In the late phase, hypothyroidism ensued, and the pituitary gland became atrophic. Using immune sera as probes in a two-dimensional immunoblotting screen followed by mass spectrometry, we identified several proteins that could function as pituitary autoantigens. These findings provide new insights into the pathogenesis of AH, and establish a platform for developing novel diagnostic biomarkers and therapeutics.

The sardinian autoimmunity study. 4. Thyroid and islet cell autoantibodies in sardinian pregnant women at delivery: a cross-sectional study.

A high incidence of autoimmune Type 1 diabetes mellitus (DM) has been clearly established in Sardinia. Although systematic epidemiological studies are still not available, an increased prevalence of thyroid autoantibodies (ATA) has been documented in the Sardinian adult population as compared to other Italian regions, suggesting that thyroid autoimmune disease may also have increased. We carried out a preliminary study with the aim of determining the prevalence of serological markers of thyroid (anti-thyroperoxydase antibodies, TPOAb) and islet cell (ICA) autoimmunity in a large number (no.=2249) of sera obtained from cord-blood of Sardinian pregnant women at delivery. The prevalence of TPOAb was 11.9%, while ICA were detected in 59 cases (2.6%). A higher prevalence of TPOAb (6/17=35.3%) was found in sera with high ICA titers (≥20 JDF-U), as compared to sera with low ICA titers (5-19 JDF-U) and to ICAnegative sera (3/42=7,1%; χ2=5.4, p=0.02 and 258/2190=11,8%; χ2=6.8, p=0.009 respectively). Fourteen women (all ICA-negative) were diabetic: 4 had Type 1 and 10 had gestational DM; due to the low number, no correlation could be established between DM type and TPOAb prevalence and/or titer. These preliminary data indicate that ATA are frequently observed in the general population of Sardinian pregnant women at term. As a consequence, even the frequency of postpartum thyroiditis is expected to be high. Although ATA were not increased in women with clinical overt diabetes, a higher prevalence of ATA was found in women with high titers of circulating ICA. Our results also confirm that Sardinia represents, perhaps for its peculiar genetic characteristics, an ideal place to study organ-specific autoimmunity.

Autoimmune Thyroid Diseases

The immune system represents the body’s main defense against substances derived from external sources (e.g., bacteria and viruses) and from abnormal processes within the body (e.g., tumor cells). These substances are collectively termed “non-self.” In order to keep the immune system in the correct range of activity, the process of non-self recognition must be highly specific and possess a memory. The specificity is conferred by peculiar receptors on the cells of the immune system able to bind foreign substances (antigens), and by the production of soluble effector proteins (antibodies) with specific antigen-recognition capacity.

Le sindromi paraneoplastiche endocrine

RiassuntoLe sindromi paraneoplastiche endocrine conseguono alla produzione da parte di neoplasie di ormoni o altre sostanze in grado di indurre manifestazioni cliniche indipendenti dal tumore primitivo stesso o dalle sue metastasi. Quantunque esistano diverse ipotesi eziopatogenetiche, al momento non ci sono elementi certi che possano spiegare la genesi di tali sindromi. Fra le manifestazioni paraneoplastiche di più frequente riscontro in ambito endocrinologico ci sono l’ipercalcemia, l’ipercorticosurrenalismo, la sindrome da inappropriata secrezione di ADH (SIADH), l’ipoglicemia e l’acromegalia paraneoplastica. La terapia, ove possibile, prevede la rimozione del tumore causale. Peraltro, trattandosi in genere di tumori maligni, la prognosi è infausta e l’approccio terapeutico è indirizzato alla normalizzazione dei parametri biochimici fuori norma, con il fine di migliorare la qualità di vita dei pazienti.