Plasma Agouti-Related Protein and Cortisol Levels in Cushing Disease: Evidence for the Regulation of Agouti-Related Protein by Glucocorticoids in Humans.

Context: Glucocorticoids regulate energy balance, in part by stimulating the orexigenic neuropeptide agouti-related protein (AgRP). AgRP neurons express glucocorticoid receptors, and glucocorticoids have been shown to stimulate AgRP gene expression in rodents. Objective: We sought to determine whether there is a relationship between plasma AgRP and hypothalamic AgRP in rats and to evaluate the relationship between cortisol and plasma AgRP in humans. Methods: We retrospectively evaluated plasma AgRP levels prior to transsphenoidal surgery in 31 patients with Cushing disease (CD) vs 31 sex- and body mass index-matched controls from a separate study. We then prospectively measured plasma AgRP, before and 6 to 12 months after surgery, in a subgroup of 13 patients with CD. Plasma and hypothalamic AgRP were measured in adrenalectomized rats with and without corticosterone replacement. Results: Plasma AgRP was stimulated by corticosterone in rats and correlated with hypothalamic AgRP expression. Plasma AgRP levels were higher in patients with CD than in controls (139 ± 12.3 vs 54.2 ± 3.1 pg/mL; P < 0.0001). Among patients with CD, mean 24-hour urine free cortisol (UFC) levels were 257 ± 39 µg/24 hours. Strong positive correlations were observed between plasma AgRP and UFC (r = 0.76; P < 0.0001). In 11 of 13 patients demonstrating surgical cure, AgRP decreased from 126 ± 20.6 to 62.5 ± 8.0 pg/mL (P < 0.05) postoperatively, in parallel with a decline in UFC. Conclusions: Plasma AgRP levels are elevated in CD, are tightly correlated with cortisol concentrations, and decline with surgical cure. These data support the regulation of AgRP by glucocorticoids in humans. AgRP's role as a potential biomarker and as a mediator of the adverse metabolic consequences of CD deserves further study.

Clinical utility of plasma POMC and AgRP measurements in the differential diagnosis of ACTH-dependent Cushing's syndrome.

CONTEXT: Distinguishing between pituitary [Cushing's disease (CD)] and ectopic causes [ectopic ACTH syndrome (EAS)] of ACTH-dependent Cushing's syndrome can be challenging. Inferior petrosal sinus sampling (IPSS) best discriminates between CD and occult EAS but is a specialized procedure that is not widely available. Identifying adjunctive diagnostic tests may prove useful. In EAS, abnormal processing of the ACTH precursor proopiomelanocortin (POMC) and the accumulation of POMC-derived peptides might be expected and abnormal levels of other neuropeptides may be detected. OBJECTIVE: The objective of the study was to evaluate the diagnostic utility of POMC measurements for distinguishing between CD and occult EAS in patients referred for IPSS. Another objective of the study was to evaluate in parallel the diagnostic utility of another neuropeptide, agouti-related protein (AgRP), because we have observed a 10-fold elevation of AgRP in plasma in a patient with EAS from small-cell lung cancer. DESIGN AND PARTICIPANTS: Plasma POMC and AgRP were measured in 38 Cushing's syndrome patients presenting for IPSS, with either no pituitary lesion or a microadenoma on magnetic resonance imaging, and in 38 healthy controls. RESULTS: Twenty-seven of 38 patients had CD; 11 of 38 had EAS. The mean POMC was higher in EAS vs CD [54.5 ± 13.0 (SEM) vs 17.2 ± 1.5 fmol/mL; P < .05]. Mean AgRP was higher in EAS vs CD (280 ± 76 vs 120 ± 16 pg/mL; P = .01). Although there was an overlap in POMC and AgRP levels between the groups, the POMC levels greater than 36 fmol/mL (n = 7) and AgRP levels greater than 280 pg/mL (n = 3) were specific for EAS. When used together, POMC greater than 36 fmol/mL and/or AgRP greater than 280 pg/mL detected 9 of 11 cases of EAS, indicating that elevations in these peptides have a high positive predictive value for occult EAS. CONCLUSIONS: Expanding upon previous observations of high POMC in EAS, this study specifically demonstrates elevated POMC levels can identify occult ectopic tumors. Elevations in AgRP also favor the diagnosis of EAS, suggesting AgRP should be further evaluated as a potential neuroendocrine tumor marker.

A lifetime of hypercalcemia and hypercalciuria, finally explained.

CONTEXT: Hypercalcemia, hypercalciuria, and recurrent nephrolithiasis are all common clinical problems. This case report illustrates a newly described but possibly not uncommon cause of this presenting complex. OBJECTIVE: We report on a patient studied for over 30 years, with the diagnosis finally made with modern biochemical and genetic tools. DESIGN AND SETTING: This study consists of a case report and review of literature conducted in a University Referral Center. PATIENT AND INTERVENTION: A single patient with hypercalcemia, hypercalciuria, and recurrent nephrolithiasis was treated with low-calcium diet, low vitamin D intake, prednisone, and ketoconazole. MAIN OUTCOME MEASURE: We measured the patient's clinical and biochemical response to interventions above. RESULTS: Calcium absorption measured by dual isotope absorptiometry was elevated at 37.4%. Serum levels of 24,25-dihydroxyvitamin D were very low, as measured in two laboratories (0.62 ng/mL [normal, 3.49 ± 1.57], and 0.18 mg/mL). Genetic analysis of CYP24A1 revealed homozygous mutation E143del previously described. The patient's serum calcium and renal function improved markedly on treatment with ketoconazole but not with prednisone. CONCLUSIONS: Chronic hypercalcemia, hypercalciuria, and/or nephrolithiasis may be caused by mutations in CYP24A1 causing failure to metabolize 1,25-dihydroxyvitamin D.

Brain Vascular Malformation Consortium: Overview, Progress and Future Directions.

Brain vascular malformations are resource-intensive to manage effectively, are associated with serious neurological morbidity, lack specific medical therapies, and have no validated biomarkers for disease severity and progression. Investigators have tended to work in "research silos" with suboptimal cross-communication. We present here a paradigm for interdisciplinary collaboration to facilitate rare disease research. The Brain Vascular Malformation Consortium (BVMC) is a multidisciplinary, inter-institutional group of investigators, one of 17 consortia in the Office of Rare Disease Research Rare Disease Clinical Research Network (RDCRN). The diseases under study are: familial Cerebral Cavernous Malformations type 1, common Hispanic mutation (CCM1-CHM); Sturge-Weber Syndrome (SWS); and brain arteriovenous malformation in hereditary hemorrhagic telangiectasia (HHT). Each project is developing biomarkers for disease progression and severity, and has established scalable, relational databases for observational and longitudinal studies that are stored centrally by the RDCRN Data Management and Coordinating Center. Patient Support Organizations (PSOs) are a key RDCRN component in the recruitment and support of participants. The BVMC PSOs include Angioma Alliance, Sturge Weber Foundation, and HHT Foundation International. Our networks of clinical centers of excellence in SWS and HHT, as well as our PSOs, have enhanced BVMC patient recruitment. The BVMC provides unique and valuable resources to the clinical neurovascular community, and recently reported findings are reviewed. Future planned studies will apply successful approaches and insights across the three projects to leverage the combined resources of the BVMC and RDCRN in advancing new biomarkers and treatment strategies for patients with vascular malformations.

Phosphaturic mesenchymal tumor, mixed connective tissue variant, of the mandible: report of a case and review of the literature.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results in renal phosphate wasting with hypophosphatemia. In most cases, the underlying cause of TIO is a small mesenchymal neoplasm that is often difficult to detect, resulting in delayed diagnosis. One such neoplasm is the phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT), an unusual entity with unique morphologic and biochemical features. Most of these tumors are found at appendicular sites with only rare cases reported in the jaws. We describe a PMTMCT involving the mandible in a patient with a protracted history of osteomalacia. A review of the current literature is provided with emphasis on the clinical and histologic features, etiopathogenesis, and management of PMTMCT in the setting of TIO.

Stroke program review group: an interim report.

The Stroke Program Review Group (SPRG) met for the first time in 2001 to identify and prioritize scientific needs and opportunities in stroke, and to consider strategies to address them. Out of this meeting came a set of scientific and resource recommendations (http://www.ninds.nih.gov/find_people/groups/stroke_prg/index.htm) including the recommendation to review progress after 5 years. In September 2006, the NINDS convened a second SPRG of prominent scientists, clinicians, industry leaders, and patient advocates to discuss progress since the first SPRG and to examine new opportunities in light of more recent advances. The report of the second SPRG meeting is found at http://www.ninds.nih.gov/find_people/groups/stroke_prg/09_2006_stroke_prg_report.htm. In this brief interim report, we list and summarize progress in each of the investigational domains outlined in the SPRG with an emphasis on those advances directly resulting from NINDS-funded research. Also listed are the top 2 or 3 research priorities for the next 5-year cycle for each investigational theme. What emerges from the first 2 reports is a clear set of priorities that have since been complemented by exciting advances that are likely to be the focus of a follow-up report from the next SPRG in 2010.

Clinical review: Rare causes of hypercalcemia.

CONTEXT: Although hypercalcemia is usually caused by primary hyperparathyroidism or malignancy, a number of other conditions can be important to consider. This review considers unusual causes of hypercalcemia that are generally not found in reviews on this subject. EVIDENCE ACQUISITION: Articles describing rarely reported associations between hypercalcemia and unusual causes were identified through a computer search of the terms hypercalcemia/etiology and through the references listed in those articles. We grouped the 58 different reports into categories defined by a presumed etiology: increased levels of 1,25-dihydroxyvitamin D or PTHrP, occult milk-alkali syndrome, and undefined mechanisms. Reports in infants and children are listed separately, as are reports of pseudohypercalcemia, situations that are not truly hypercalcemic because the ionized calcium is normal. EVIDENCE SYNTHESIS: In some situations, as this review points out, a number of unusual causes of hypercalcemia are important to consider. The search for an elusive cause of hypercalcemia is best accomplished by the most likely potential mechanism. An orderly search in this manner is likely to reveal the underlying cause. CONCLUSIONS: That so many patients have been described with rare and usually poorly understood causes of hypercalcemia highlights our incomplete understanding of calcium metabolism in humans and suggests additional areas in which directed clinical investigation might improve our knowledge of the normal metabolism of calcium.