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We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

We present the clinical and pathologic features of two patients with juvenile dermatomyositis (DM) with severe gastrointestinal ulceration or perforation who required surgery. Abdominal pain which is persistent, progressive or severe, even in patients with improving or mildly active juvenile DM, should be carefully evaluated. The absence of occult blood in the stool and normal radiographs do not exclude these potentially serious complications. Chronic endarteropathy, not an acute vasculopathy previously reported, is the pathology associated with the ischemic ulceration in these patients. The current approach to treatment of juvenile DM with immunosuppressive agents may have contributed to delay in the onset of these gastrointestinal manifestations and to their pathologic features.

Objective To define the relative importance (RI) of class II major histocompatibility complex (MHC) alleles and peptide binding motifs as risk or protective factors for juvenile dermatomyositis (DM), and to compare these with HLA associations in adult DM. Methods DRB1 and DQA1 typing was performed in 142 Caucasian patients with juvenile DM, and the results were compared with HLA typing data from 193 patients with adult DM and 797 race-matched controls. Random Forests classification and multiple logistic regression were used to assess the RI of the HLA associations. Results The HLA–DRB1*0301 allele was a primary risk factor (odds ratio [OR] 3.9), while DQA1*0301 (OR 2.8), DQA1*0501 (OR 2.1), and homozygosity for DQA1*0501 (OR 3.2) were additional risk factors for juvenile DM. These risk factors were not present in patients with adult DM without defined autoantibodies. DQA1 alleles *0201 (OR 0.37), *0101 (OR 0.38), and *0102 (OR 0.51) were identified as novel protective factors for juvenile DM, the latter 2 also being protective factors in adult DM. The peptide binding motif DRB1 9EYSTS13 was a risk factor, and DQA1 motifs F25, S26, and 45(V/A)W(R/K)47 were protective. Random Forests classification analysis revealed that among the identified risk factors for juvenile DM, DRB1*0301 had a higher RI (100%) than DQA1*0301 (RI 57%), DQA1*0501 (RI 42%), or the peptide binding motifs. In a logistic regression model, DRB1*0301 and DQA1*0201 were the strongest risk and protective factors, respectively, for juvenile DM. Conclusion DRB1*0301 is ranked higher in RI than DQA1*0501 as a risk factor for juvenile DM. DQA1*0301 is a newly identified HLA risk factor for juvenile DM, while 3 of the DQA1 alleles studied are newly identified protective factors for juvenile DM.

No variant of multiple endocrine neoplasia type 1 (MEN1) has been reproducible among families. We examined two large kindreds with MEN1 variants, and we compared these to past reports. The two kindreds were followed up for 20-30 yr with MEN1 tumors in 30 members. Results in cases from two kindreds were that 93% showed parathyroid adenoma, 40% pituitary tumor (always prolactinoma), and 27% enteropancreatic endocrine tumor. The latter included 10% insulinoma, 7% nonfunctioning islet tumor, but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs. 42%, P < 0.01) and higher prevalence of prolactinoma (40% vs. 22%, P < 0.01) define this variant. Many possible biases of retrospective analyses were excluded as possible explanations. Previously sequenced DNA showed no characteristic MEN1 mutation in these two kindreds and in a third, reported previously; the lack of any shared MEN1 mutation also excluded common ancestry for MEN1 among the three kindreds. The causes for differences between this variant and typical MEN1 are unknown. In conclusion, this variant shows more frequent prolactinoma and less frequent gastrinoma than typical MEN1; the variant is reproducible among kindreds. MEN1 carriers in such families should have periodic monitoring adjusted for the expected penetrance of tumors.

Objective To use a core set of outcome measures to develop preliminary definitions of improvement for adult and juvenile myositis as composite end points for therapeutic trials. Methods Twenty-nine experts in the assessment of myositis achieved consensus on 102 adult and 102 juvenile paper patient profiles as clinically improved or not improved. Two hundred twenty-seven candidate definitions of improvement were developed using the experts' consensus ratings as a gold standard and their judgment of clinically meaningful change in the core set of measures. Seventeen additional candidate definitions of improvement were developed from classification and regression tree analysis, a data-mining decision tree tool analysis. Six candidate definitions specifying percentage change or raw change in the core set of measures were developed using logistic regression analysis. Adult and pediatric working groups ranked the 13 top-performing candidate definitions for face validity, clinical sensibility, and ease of use, in which the sensitivity and specificity were ≥75% in adult, pediatric, and combined data sets. Nominal group technique was used to facilitate consensus formation. Results The definition of improvement (common to the adult and pediatric working groups) that ranked highest was 3 of any 6 of the core set measures improved by ≥20%, with no more than 2 worse by ≥25% (which could not include manual muscle testing to assess strength). Five and 4 additional preliminary definitions of improvement for adult and juvenile myositis, respectively, were also developed, with several definitions common to both groups. Participants also agreed to prospectively test 6 logistic regression definitions of improvement in clinical trials. Conclusion Consensus preliminary definitions of improvement were developed for adult and juvenile myositis, and these incorporate clinically meaningful change in all myositis core set measures in a composite end point. These definitions require prospective validation, but they are now proposed for use as end points in all myositis trials.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder characterized by multiple parathyroid, pancreatic, duodenal, and pituitary neuroendocrine tumors. Nonendocrine mesenchymal tumors, such as lipomas, collagenomas, and angiofibromas have also been reported. MEN1-associated neuroendocrine and some mesenchymal tumors have documented MEN1 gene alterations on chromosome 11q13. To test whether the MEN1 gene is involved in the pathogenesis of multiple smooth muscle tumors, we examined the 11q13 loss of heterozygosity (LOH) and clonality patterns in 15 leiomyomata of the esophagus, lung, and uterus from five patients with MEN1. Forty sporadic uterine leiomyomata were also studied for 11q13 LOH. LOH analysis was performed using four polymorphic DNA markers at the MEN1 gene locus; D11S480, PYGM, D11S449 , and INT-2 . 11q13 LOH was detected in 10 of 12 (83%) MEN1-associated esophageal and uterine smooth muscle tumors. In contrast, LOH at the MEN1 gene locus was demonstrated only in 2 of 40 (5%) sporadic uterine tumors. LOH at 11q13 was not documented in three lung smooth muscle tumors from a single patient with MEN1. Ten tumors from two female patients were additionally assessed for clonality by X-chromosome inactivation analysis. The results demonstrated different clonality patterns in multiple tumors in the same organ in each individual patient. The data indicate that leiomyomata of the esophagus and uterus in MEN1 patients arise as independent clones, develop through MEN1 gene alterations, and are an integral part of MEN1. However, the MEN1 gene is not a significant contributor to the tumorigenesis of sporadic uterine leiomyomata.

To study tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1) cytokine polymorphisms as possible risk and protective factors, define their relative importance, and examine these as severity factors in patients with juvenile dermatomyositis (DM).TNFalpha and IL-1 cytokine polymorphism and HLA typing were performed in 221 Caucasian patients with juvenile DM, and the results were compared with those in 203 ethnically matched healthy volunteers.The genotypes TNFalpha -308AG (odds ratio [OR] 3.6), TNFalpha -238GG (OR 3.5), and IL-1alpha +4845TT (OR 2.2) were risk factors, and TNFalpha -308GG (OR 0.26) as well as TNFalpha -238AG (OR 0.22) were protective, for the development of juvenile DM. Carriage of a single copy of the TNFalpha -308A (OR 3.8) or IL-1beta +3953T (OR 1.7) allele was a risk factor, and the TNFalpha -238A (OR 0.29) and IL-1alpha +4845G (OR 0.46) alleles were protective, for juvenile DM. Random Forests classification analysis showed HLA-DRB1*03 and TNFalpha -308A to have the highest relative importance as risk factors for juvenile DM compared with the other alleles (Gini scores 100% and 90.7%, respectively). TNFalpha -308AA (OR 7.3) was a risk factor, and carriage of the TNFalpha -308G (OR 0.14) and IL-1alpha -889T (OR 0.41) alleles was protective, for the development of calcinosis. TNFalpha -308AA (OR 7.0) was a possible risk factor, and carriage of the TNFalpha -308G allele (OR 0.14) was protective, for the development of ulcerations. None of the studied TNFalpha, IL-1alpha, and IL-1beta polymorphisms were associated with the disease course, disease severity at the time of diagnosis, or the patient's sex.TNFalpha and IL-1 genetic polymorphisms contribute to the development of juvenile DM and may also be indicators of disease severity.

We describe the clinical features of 28 patients with juvenile dermatomyositis (JDM) and 1 patient with adult-onset dermatomyositis (DM), all of whom developed lipodystrophy (LD) that could be categorized into 1 of 3 phenotypes, generalized, partial, or focal, based on the pattern of fat loss distribution. LD onset was often delayed, beginning a median of 4.6 years after diagnosis of DM. Calcinosis, muscle atrophy, joint contractures, and facial rash were DM disease features found to be associated with LD. Panniculitis was associated with focal lipoatrophy while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more associated with generalized LD. Specific LD features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with LD, in a gradient of frequency and severity among the 3 sub-phenotypes. Metabolic studies frequently revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial LD. Regional fat loss from the thighs, with relative sparing of fat loss from the medial thighs, was more frequent in generalized than in partial LD and absent from DM patients without LD. Cytokine polymorphisms, the C3 nephritic factor, insulin receptor antibodies, and lamin mutations did not appear to play a pathogenic role in the development of LD in our patients. LD is an under-recognized sequela of JDM, and certain DM patients with a severe, prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for the development of this complication. High-risk JDM patients should be screened for metabolic abnormalities, which are common in generalized and partial LD and result in much of the LD-associated morbidity. Further study is warranted to investigate the pathogenesis of acquired LD in patients with DM.