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Autoimmune Addison's disease (AAD) is a rare condition occurring either in isolation or associated with other autoimmune diseases as part of an autoimmune polyglandular syndrome (APS) type 1, 2 or 4. Multiple endocrine neoplasia (MEN) type 1, 2 or 4 is a hereditary autosomal dominant cancer syndrome. Medullary thyroid carcinoma and pheochromocytoma are neoplasms common to MEN-2a and MEN-2b. We describe a unique, complex case of a man resulted affected by both APS-2 and MEN-2a. The patient developed Hashimoto's thyroiditis, diabetes mellitus type 1 and AAD, despite testing negative for adrenal cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21-OHAb). Moreover, he had also a family history for MEN-2a and he first developed medullay thyroid cancer, then bilateral pheochromocytoma on the adrenal substrate of an AAD. On adrenal histology we found complete bilateral cortical atrophy in the presence of a lymphocytic infiltration and fibrosis, confirming an ACA and 21-OHAb-negative AAD. This datum is the first documented in a living individual and confirms that the absence of autoantibodies is not incompatible with an autoimmune disease and confirms that AAD is a cell-mediated autoimmune disease limited to the adrenal cortex and sparing medullary. In the light of a literature review concerning the association between APS and MEN, this is the first proven case to be reported in humans. Finally, our findings suggest that adrenal medullary tumor can develop even on an adrenal gland with cortical atrophy due to autoimmune adrenalitis.

Autoinflammatory diseases are caused by inflammasome dysregulation leading to overproduction of proinflammatory cytokines and a pathological delay in the inflammation switching off. The progress of cellular biology has partially clarified pathogenic mechanisms behind monogenic autoinflammatory diseases, whereas little is known about the polygenic ones. Although the genetic susceptibility of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is still obscure, the presence of overlapping symptoms with monogenic periodic fevers, the recurrence in family members, the important role played by dysregulated interleukin- (IL-) 1β secretion during flares, the overexpression of inflammasome-associated genes during attacks, and, last but not least, the therapeutic efficacy of IL-1β blockade strongly indicate a potential genetic involvement in its pathogenesis, probably linked with environmental factors. PFAPA syndrome has a typical inception in the pediatric age, but a delayed onset during adulthood has been described as well. Treatments required as well as effectiveness of tonsillectomy remain controversial, even if the disease seems to have a self-limited course mostly in children. The purpose of this review is to provide an overview of this complex polygenic/multifactorial autoinflammatory disorder in which the innate immune system undoubtedly plays a basic role.

Basic fibroblast growth factor (bFGF) is a potent endothelial cell mitogen found in a variety of normal and tumor tissues. bFGF lacks a classical amino-terminal signal sequence and is not readily detectable in plasma from normal subjects. In earlier studies we showed increased bFGF-like mitogenic activity for parathyroid-derived endothelial cells and (increased) bFGF immunoreactivity (0.24-1.28 ng/mL) in plasma of subjects with multiple endocrine neoplasia type 1 (MEN-1). In the present study we examined the proliferative activity of MEN-1 and normal plasmas (applied to protein-A columns) in calf pulmonary artery endothelial cells. Protein-A-eluted activity in plasma from MEN-1 prolactinoma plasma exceeded activity from normal and MEN-1 nonprolactinoma plasma in three of eight MEN-1 subjects with untreated or recurrent prolactinoma. Protein-A-eluted active fractions from MEN-1 prolactinoma plasma had several properties of an immunoglobulin G, including affinity for antihuman immunoglobulin G (IgG) agarose, sensitivity to thiols, and (prepared by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions) apparent mol wt corresponding to those of the heavy and light chains of IgG. The IgG fraction of MEN-1 prolactinoma plasma had far more activity in endothelial cells than did optimal concentrations of known growth factors or conditioned medium from prolactinoma cells. Endothelial cell bioactivity in protein-A-eluted fractions from MEN-1 prolactinoma plasma was neutralized 70% by rabbit antibodies to intact bFGF. These results imply novel growth stimulatory bFGF-like autoantibodies in a subset of MEN-1 patients with prolactinoma.

The basic fibroblast growth factor-like mitogen detected in the plasma of patients with the multiple endocrine neoplasia type 1 (MEN-1) syndrome was found to have a specific mitogenic effect on parathyroid endothelial cells in vitro. To investigate its pathogenic role in humans, the endothelial component of parathyroid glands was evaluated by ultrastructural morphometry in six MEN-1 patients. The results were compared with those found in six patients with uremic hyperparathyroidism (UHPT) and in three subjects with histologically normal glands. Plasma mitogenic activity was found in all MEN-1 patients but not in those with UHPT or in normal subjects. All morphometric parameters investigated (fractional volume and nuclear density of capillary endothelial cells, volume fraction and number per unit area of capillaries) showed 1.5- to 2-fold higher values in patients with MEN-1 than in those with UHPT (P < 0.05). In contrast, no difference was found between MEN-1 cases and normal subjects. Quantitative evaluation of parathyroid pericytes yielded results similar to those of endothelial cells. These data indicate that the proliferation of parathyroid cells in MEN-1 patients is accompanied by parallel increase in the associated endothelial component that does not occur in patients with UHPT and may support the hypothesis of an in vivo role of the MEN-1 mitogen factor on the endothelial component of parathyroid glands in MEN-1 patients.

After mastectomy and radiation for breast cancer, two patients were found to have persistent elevated CEA in their serum. This finding was erroneously attributed to occult metastases for the first patient and to local recurrence for the second. Overlooked medullary thyroid carcinoma (MTC) was the causal disease in both patients. A review of the literature stresses the frequency of CEA elevation in serum of MTC patients. A thorough search for any possible cause of elevated levels of CEA is advocated, particularly by thyroid sonogram with a needle aspiration biopsy when a nodule is discovered and by calcitonin assay in the serum.

Basic fibroblast growth factor (bFGF) is a potent endothelial cell mitogen found in a variety of normal and tumor tissues. Basic FGF lacks a classical signal sequence, and it is not clear how it is released from cells. bFGF or bFGF-like activity has not been previously demonstrated in plasma. In an earlier study we showed increased mitogenic activity for parathyroid-derived epithelial and mesenchymal cells in plasma of subjects with familial multiple endocrine neoplasia type 1 (FMEN1). In the present study we examined the growth-promoting activity of normal and FMEN1 plasmas [applied to heparin-Sepharose (HS) columns] in parathyroid-derived cloned endothelial cells. FMEN1 plasma HS-adsorbed activity exceeded normal plasma HS-adsorbed activity in 6 of 8 FMEN1 plasma samples. Peak (FMEN1 plasma) HS-adsorbed activity eluted with 0.1-0.3 M NaCl, was completely neutralized by specific antibodies against bFGF, and had an apparent mol wt of 110 kD. Active fractions from FMEN1 plasma prepared by gel filtration in 7 M urea displayed apparent mol wt of about 14-16 kD and showed increased apparent affinity for HS; recovered activity appeared principally in the 3.0-M NaCl eluate. Using a sensitive two-site immunoradiometric assay for bFGF we found 0.4 ng/mL bFGF-like immunoreactivity in the highly purified 3.0-M NaCl eluate from a HS column to which the active components from gel filtration of FMEN1 plasma in 7 M urea were applied. These results imply that bFGF or closely related factors circulate in FMEN1.

A multiple endocrine neoplasia type Ia patient who initially had a calcitonin-rich medullary thyroid carcinoma followed an indolent clinical course for 7 years after surgical resection. Sudden rapid dissemination of tumor led to death 2 years later. At autopsy, calcitonin immunostaining of tumor was diffusely negative, with slight positivity in less than 5% of cells. The loss of a marker of differentiation in association with the marked change in the clinical course suggests the development within the well-differentiated tumor of a poorly differentiated, biologically aggressive population of tumor cells.

We compared three different scintigraphic techniques for the localization of neck recurrences and metastases in seven patients with medullary thyroid carcinoma one month to eight years after the first surgical intervention. Three successive scintigraphic studies were performed in five patients (6 x 3 studies) within two weeks using 201Tl chloride, 111In-labeled F(ab')2 fragments of the anti-carcinoembryonic antigen (anti-CEA) monoclonal antibody (MoAb) BW 431/31, and 131I meta-iodo-benzylguanidine (MIBG). Additionally, 11 studies were performed with the 111In-labeled MoAb fragment BW 431/31 (seven studies) or the 99mTc-labeled intact anti-CEA MoAb BW 431/26 (four studies). The gold standards for classifying scintigraphic results were biopsy, histology, surgery, and cytology. Six regions were classified as positive or negative in each study: thyroid region, four quadrants (lymph node regions) around the thyroid, and the region of the upper mediastinum. Of 36 sites, 201Tl was true positive (TP) in seven sites, false-positive (FP) in one site, true negative (TN) in 22 sites, and false-negative (FN) in six sites, resulting in a sensitivity of 54% and a specificity of 96%. 131I MIBG was TP in four sites, FP in none of the sites, TN in 23 sites, and FN in nine sites, with a sensitivity of 31% and a specificity of 100%. Immunoscintigraphy (102 sites overall) was TP in 16 sites, FP in five sites, TN in 77 sites, and FN in four sites, resulting in a sensitivity of 80% and a specificity of 94%. Immunoscintigraphy with 111In/99mTc anti-CEA F(ab')2 fragment/intact antibody is superior to scintigraphy with 201Tl and 131I MIBG.