Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.

Context:It is unclear whether patients with asymptomatic primary hyperparathyroidism (PHPT) do better with parathyroidectomy (PTx) as compared with conservative medical management. Objective:The aim of the study was to evaluate the beneficial effect of PTx vs. conservative management in patients with mild asymptomatic PHPT. Design:We conducted a prospective, randomized study. Setting:The study took place at a referral center. Patients:We studied 50 patients who did not meet any guidelines for parathyroid surgery as recommended by the National Institutes of Health Consensus Development Conference on Asymptomatic PHPT.Intervention: Patients were randomly assigned to PTx or no PTx and were evaluated at 6 months and at 1 yr. Main Outcome Measures:We compared changes (percentage of basal) of lumbar spine bone mineral density (BMD) between the two groups at 1 yr. Results:The change in BMD at lumbar spine was greater after PTx (ϩ4.16 Ϯ 1.13 for PTx vs. Ϫ1.12 Ϯ 0.71 for no PTx; P ϭ 0.0002). The change in BMD at the total hip was also significantly greater in the PTx group (ϩ2.61 Ϯ 0.71 for PTx vs. Ϫ1.88 Ϯ 0.60 for no PTx; P ϭ 0.0001). There was no difference in BMD after 1 yr between both groups at the one-third radius site. In comparison with those who did not undergo surgery, the PTx subjects, after 1 yr, showed significant differences in four quality of life measures as determined by the 36-item short form health survey scale: bodily pain (P ϭ 0.001), general health (P ϭ 0.008), vitality (P ϭ 0.003), and mental health (P ϭ 0.017). Conclusions:In patients with mild asymptomatic PHPT, successful PTx is followed by an improvement in BMD and quality of life.

Primary hyperparathyroidism (PHPT) is a common disorder in which parathyroid hormone (PTH) is excessively secreted from one or more of the four parathyroid glands. A single benign parathyroid adenoma is the cause in most people. However, multiglandular disease is not rare and is typically seen in familial PHPT syndromes. The genetics of PHPT is usually monoclonal when a single gland is involved and polyclonal when multiglandular disease is present. The genes that have been implicated in PHPT include proto-oncogenes and tumour-suppressor genes. Hypercalcaemia is the biochemical hallmark of PHPT. Usually, the concentration of PTH is frankly increased but can remain within the normal range, which is abnormal in the setting of hypercalcaemia. Normocalcaemic PHPT, a variant in which the serum calcium level is persistently normal but PTH levels are increased in the absence of an obvious inciting stimulus, is now recognized. The clinical presentation of PHPT varies from asymptomatic disease (seen in countries where biochemical screening is routine) to classic symptomatic disease in which renal and/or skeletal complications are observed. Management guidelines have recently been revised to help the clinician to decide on the merits of a parathyroidectomy or a non-surgical course. This Primer covers these areas with particular attention to the epidemiology, clinical presentations, genetics, evaluation and guidelines for the management of PHPT.

We investigated the involvement of the HRPT2 gene by loss of heterozygosity analysis and direct sequencing in a kindred with hyperparathyroidism-jaw tumor syndrome (HPT-JT) and three kindreds with familial isolated primary hyperparathyroidism (FIHP). Seven patients with sporadic parathyroid cancers and 35 with parathyroid adenomas with no family history of primary hyperparathyroidism or HPT-JT were also studied. A germline heterozygous substitution G to A was found in the donor splice site of intron 1 in one of the three FIHP families. No mutations were identified in the HPT-JT kindred. A somatic HRPT2 mutation was found in four of seven patients with parathyroid cancers, two of which were unreported frameshift mutations (195insT and 195insA) in exon 2. Consistent with recent findings, two of seven patients with sporadic parathyroid cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in one. In conclusion, we provide additional evidence for a strong association between HRPT2 gene mutations and sporadic parathyroid cancer. The finding that two of the seven patients with sporadic parathyroid cancer carried an HRPT2 germline mutation suggests that they might have occult HPT-JT. Our results also confirm the need for testing HRPT2 gene in FIHP families.

The clinical usefulness of thyroid ultrasonography in the evaluation of patients with autoimmune thyroiditis has been investigated. Thyroid ultrasonography was performed in 1184 consecutive patients attending our clinic, and the echo density of the thyroid parenchyma was evaluated with respect to that of normal thyroid tissue. Diffuse thyroid hypoechogenicity was found in 44 of 238 (18.5%) patients with autoimmune thyroiditis; the degree of hypoechogenicity was significantly correlated with the levels of circulating thyroid autoantibodies. Thyroid function was normal in all 194 patients with normal thyroid echogenicity, whereas hypothyroidism was found in 28 of 44 (63.6%) with reduced thyroid echogenicity. Included in this group were 8 patients, euthyroid at the first observation, who developed hypothyroidism over an 18-month follow-up period. None of the 133 patients with autoimmune thyroiditis and normal thyroid echogenicity followed for the same period of time became hypothyroid. Evidence of diffuse lymphocytic thyroiditis was obtained by histology after thyroidectomy (n = 10) or multiple fine needle aspiration cytology (n = 15) in 25 of the 44 patients with thyroid hypoechogenicity; on the other hand, focal thyroiditis was shown at histology in 8 patients who had normal thyroid echogenicity. In conclusion, diffuse low thyroid echogenicity was found in about 20% of patients with autoimmune thyroiditis. This echographic pattern is indicative of diffuse autoimmune involvement of the gland and is associated with or may predict the development of hypothyroidism.

From 1969 to 1990 there were 309 patients with differentiated thyroid carcinoma (241 papillary and 68 follicular) treated with radioactive iodine for functioning node metastases alone (n = 191) or distant metastases (n = 118) with or without node metastases. These patients represented 32.7% of 945 patients treated in our institution during the same period. Initial treatment included near-total thyroidectomy and 131I ablation of postsurgical thyroid residue, followed by L-thyroxine suppressive therapy. At the end of follow-up (mean 5.8 years), 146 patients (76.4%) in the group with nodal metastases were considered cured, as assessed by clinical and laboratory evaluation including whole body scan (WBS) and serum thyroglobulin (Tg) levels; 32 patients (16.7%) had persistent disease. Loss of 131I uptake in persistent metastatic lesions occurred in five patients (2.6%), and newly developed distant metastases occurred in eight patients (4.2%). Of the patients with distant metastases, 36.4% were cured by 131I. Distant metastases from papillary carcinomas had a higher cure rate than follicular carcinomas (p < 0.01). The metastases of four patients (5.2%) lost the property to take up radioiodine. Lung and bone metastases detectable by WBS but not by radiography were most likely to be cured by 131I. The overall survival at the end of follow-up was 95.8% in patients with only lymph node metastases and 76.0% in those with distant metastases. Tumor-related deaths were 3.6% and 23.7%, respectively. Our data indicate that 131I therapy is highly effective in the treatment of lymph node metastases from differentiated thyroid carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

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The treatment of choice is the en bloc resection of the tumor. The course of PC is variable; most patients have local recurrences or distant metastases and die from unmanageable hypercalcemia.