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.

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.

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 Address reprint requests to: Lisa G. Rider, MD, Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, CRC 4-2352, MSC 1301, 10, Center Drive, Bethesda, MD 20892-1301. Fax: 301-451-5588; email: E-mail: riderl@mail.nih.gov. * These authors contributed equally to this work. † Contributors to this study are listed in the appendix. NIH Public AccessAuthor Manuscript Medicine (Baltimore) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 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.

The investigation of familial isolated hyperparathyroidism (FIHP) has been greatly facilitated in recent years by the identification of the genes responsible for most cases of syndromic familial hyperparathyroidism (HPT). Kindreds with apparently isolated hyperparathyroidism have been evaluated with clinical, biochemical, imaging and gene mutational tests designed to recognize multiple endocrine neoplasia type 1 (MEN1), the hyperparathyroidism-jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). Approximately 100 kindreds with the apparent diagnosis of FIHP were studied in clinical series that included screening by germline DNA mutational testing of one or more of the genes for these three syndromes since 1997. Of these provisionally diagnosed FIHP kindreds, some 10 to 20% had occult MEN1 and roughly 10% each had unrecognized HPT-JT or an FHH-related disorder evidenced by mutation of the calcium sensing receptor. Thus nearly 70% of FIHP kindreds are apparently non-syndromic. Even accounting for the likely underestimation in this group of syndromic causes for familial HPT due to shortcomings in current clinical and gene mutational testing methods, this finding suggests the majority of FIHP kindreds have no currently recognized syndromic etiology. Further study of this subset of carefully evaluated and apparently non-syndromic FIHP kindreds should assist in the identification of novel gene(s) important for neoplasia in the parathyroid and whose mutation can result in the FIHP phenotype.