ABSTRACT
PURPOSE: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). DESIGN: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. MAIN OUTCOME ANALYSIS: Clinical, genetic, and functional associations were determined. RESULTS: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. CONCLUSIONS: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.
Subject(s)
Adrenal Gland Neoplasms/genetics , Membrane Proteins/genetics , Pheochromocytoma/genetics , Adrenal Gland Neoplasms/epidemiology , Adult , Aged , Aged, 80 and over , Cohort Studies , Databases, Genetic , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Testing , Germ-Line Mutation , Humans , Male , Middle Aged , Pheochromocytoma/epidemiology , Retrospective Studies , Young AdultABSTRACT
BACKGROUND Hypercalcemia associated with chronic myeloid leukemia (CML) is an ominous sign. Although rare, several cases have been reported and multiple pathophysiologic mechanisms have been independently proposed. We present a patient case and a literature review of the clinical presentation and mechanisms of CML-associated hypercalcemia. CASE REPORT A 58-year-old male with a past medical history of CML diagnosed six years earlier, presented to the emergency department with one week of acute confusion, disorientation, polyuria, and polydipsia. On physical examination, we observed tachycardia, altered mental status, and dehydration. Blood analysis revealed leukocytosis, thrombocytosis, and marked hypercalcemia (18.6 mg/dL). His chest CT scan showed diffuse lytic lesions and bone destruction concerning for diffuse bone marrow involvement. The patient was diagnosed with hypercalcemia in the context of a CML blast phase. Treatment with hydration, calcitonin, and zoledronic acid lead to control of his symptoms and normalization of his serum calcium levels. After discharged, the patient was maintained on palliative treatment and zoledronic acid management without new episodes of hypercalcemia. However, eight months later, the patient died. CONCLUSIONS Evidence from the literature demonstrates a highly variable clinical presentation of CML-associated hypercalcemia, commonly occurring during an accelerated or a blast phase, and associated with poor survival. Multiple mechanisms could be involved and are not exclusive of each other. Better understanding of the pathophysiologic mechanisms involved in CML-associated hypercalcemia could lead to improvement in clinical and laboratory evaluation of these patients and be the foundation for the development of better management strategies and possibly target-directed therapy to positively improve prognosis.
Subject(s)
Blast Crisis/pathology , Bone Density Conservation Agents/therapeutic use , Calcitonin/therapeutic use , Diphosphonates/therapeutic use , Hypercalcemia/drug therapy , Hypercalcemia/etiology , Imidazoles/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Blast Crisis/blood , Disease Progression , Drug Therapy, Combination , Fatal Outcome , Humans , Hypercalcemia/diagnosis , Male , Middle Aged , Zoledronic AcidSubject(s)
Adrenal Insufficiency/diagnosis , Acute Disease , Adrenal Insufficiency/diagnostic imaging , Aged , Humans , Male , RadiographyABSTRACT
Graduates of military internal medicine residency programs are required to have the necessary knowledge and skills to function as internists, military physicians, and military medical leaders. The global war on terrorism has increased the role internists are playing in combat theaters as they fill multiple different military medical positions including battalion, brigade, and division surgeons as well as physicians in echelon I, II, and III medical facilities. Along with general internists, internal medicine subspecialists, pediatricians, and family physicians also fill these roles. Although internal medicine training provides a broad-based knowledge to care for adults, it does not provide significant training in combat casualty care, detainee health care, or environmental health. To overcome many of these perceived shortfalls, we developed the 3-day deployment course for graduating internal medicine residents outlined in this article. Through a combination of didactic and hands-on training, militarily relevant medical knowledge and skills necessary to function at echelon I and II levels of care were provided. Residents uniformly accepted the course with measurable increase in their fund of knowledge at the completion of the course.
Subject(s)
Curriculum , Internal Medicine/education , Internship and Residency , Military Medicine/education , Warfare , Adult , Clinical Competence , Humans , Middle Aged , Military Personnel/education , United StatesABSTRACT
PURPOSE: The aim of this study was to compare glycemic control with either regular or lispro insulin sliding scales in hospitalized Type 2 diabetics who were not using insulin as outpatients. METHODS: Forty-three patients with Type 2 diabetes, who were taking oral agents only, were admitted to a medical inpatient service and randomized to receive either regular or lispro insulin sliding scale. Oral agents for diabetes were held upon admission and patients were followed throughout their hospital stay. RESULTS: There was no significant difference (P>.05) between the average finger-stick blood glucose (FSBG) in the regular insulin group (157.78+/-40.16 mg/dl) and the lispro insulin group (152.04+/-27.71 mg/dl). No significant difference was found between the daily dose of insulin (regular, 5.83+/-5.01 units; lispro, 4.27+/-3.40 units), total amount of insulin used during hospitalization (regular, 11.87+/-10.78 units; lispro, 12.77+/-14.39 units), glucose excursion (regular, 110.13+/-25.86 mg/dl; lispro, 106.77+/-52.65 mg/dl), or length of hospital stay (regular, 2.33+/-1.23 days; lispro, 2.69+/-1.59 days). CONCLUSION: No significant difference in glycemic control was found in hospitalized Type 2 diabetic patients who received either regular or lispro insulin sliding scales. Both insulin sliding scales used in this study are inadequate to achieve current recommended glycemic targets in this patient population, when used as the only inpatient treatment for diabetes.
Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/drug therapy , Insulin/analogs & derivatives , Insulin/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Fructosamine/blood , Glycated Hemoglobin/analysis , Hospitalization , Humans , Insulin Lispro , Length of Stay , Male , Middle AgedABSTRACT
OBJECTIVE: To present a case of the "hook effect" occurring in the prolactin immunoassay in a patient with giant prolactinoma and to review this phenomenon. METHODS: We describe the clinical, biochemical, radiologic, and pathologic data of a patient with a giant prolactinoma, in which dilution testing of serum prolactin levels confirmed the presence of the hook effect. We discuss the historical and mechanistic aspects of the hook effect and then review its occurrence with the prolactin assay. RESULTS: A 65-year-old man sought medical attention because of headaches, personality changes, and "bulging" eyes. Cranial magnetic resonance imaging disclosed a 10-cm-diameter, lobulated, heterogeneous, locally invasive mass in the anterior skull base and cranial fossa. Initial laboratory testing showed a prolactin level of 164.5 ng/mL (normal range, 1.6 to 18.8). The pathology specimen from his surgical debulking procedure was consistent with prolactinoma. Retesting of the original serum prolactin sample with serial dilutions revealed a prolactin level of 26,000 ng/mL. A postoperative diluted prolactin level was 22,000 ng/mL. Both prolactin samples demonstrated the hook effect. Dopamine agonist therapy was initiated, and the prolactin level and size of the tumor decreased substantially. The hook effect most commonly occurs when excess antigen (for example, prolactin) is present during testing. Dilution testing can counteract this assay phenomenon. CONCLUSION: Clinicians should be aware of this laboratory phenomenon when evaluating large pituitary or parasellar masses. When the hook effect is suspected, dilution testing of prolactin samples may prevent incorrect diagnosis and unnecessary surgical intervention in patients with prolactinomas.