The Carotid Body: A Pathologist's View

A review of the literature on the histogenesis and function of the carotid body suggests that the results and the original interpretations of embryological, histological and histochemical investigations have not provided a convincing explanation of the origin of this structure. That the carotid body is developed from mesoderm and is a sensory organ (chemoreceptor) seems unlikely because of: morphological similarities between some of the carotid body tumours and certain tumours of peripheral nerves; certain electron microscopic similarities between the cells of carotid body and adrenal medulla; chromatographic demonstration of catecholamines in the human carotid bodies; and contradictory results of both animal experiments and clinical observations concerning function of this structure.It is concluded that the carotid body arises from ectoderm and should probably be classified as a gland of internal secretion, related to the adrenal medulla and other paraganglia.     

Primary Hyperparathyroidism During Pregnancy: A Case Series of 8 Patients

Objective: Due to a lack of typical clinical manifestations and physiologic changes in calcium metabolism during pregnancy, primary hyperparathyroidism (PHPT) during pregnancy is commonly underdiagnosed, and treatment during this unique period presents a clinical challenge. Hence, the aim of the present study was to summarize the cases of 8 pregnant patients with PHPT who were treated at our center to provide better clinical insight into this condition.Methods: Our study comprised a retrospective analysis of 8 pregnant PHPT patients and a control group of 22 age-matched, nonpregnant PHPT patients during the same period. Clinical manifestations, biochemical indices, pathologic types, therapeutic strategies, and pregnancy outcomes were compiled, and 25 patients were screened for germline mutations in the MEN1, CDC73, and CaSR genes.Results: The most-common symptoms in the pregnancy group involved the gastrointestinal tract (GIT) in 7/8 cases (87.5%), followed by urinary system involvement (50%) and joint pain (50%). In contrast, GIT symptoms in the control group were significantly less common (31.82%; P = .012). There was a trend of more-severe elevation of serum parathyroid hormone levels in the control group compared to that in the pregnancy group (P = .053). No differences were found in blood-ionized calcium, phosphate, or alkaline phosphatase levels between the two groups. In the pregnancy group, the serum albumin-corrected calcium level was reduced from 3.42 ± 0.66 mmol/L to 2.89 ± 0.46 mmol/L (P = .025) after hydration and medical treatment. Six patients, three of whom were in the second trimester of pregnancy, underwent parathyroidectomy, and 3 patients were after childbirth or had induced labor. Postoperative serum calcium levels were reduced to within the normal range. Fetal/neonatal complications were observed in 4 of 5 patients who had not received surgical treatment during pregnancy. In addition, 2 of 5 pregnant PHPT patients were found to carry MEN1 mutations, whereas no mutations were detected in any of the 20 nonpregnant patients.Conclusion: In this case series of PHPT during pregnancy, the most-common complaint of GIT symptoms may be easily confused with pregnancy reactions, which might contribute to the under- or misdiagnosis of this clinical entity. Patients who did not receive surgical treatment during pregnancy had high incidences of fetal/neonatal complications and worse pregnancy outcomes.Abbreviations: CaSR = calcium-sensing receptor; CDC73 = cell division cycle 73; GIT = gastrointestinal tract; MEN = multiple endocrine neoplasia; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; SCa = serum calcium     

Evaluation of Body Composition in Patients With and Without Adrenal Tumors and Without Overt Hypersecretory Syndromes

ObjectiveTo compare body composition between patients with autonomous cortisol secretion (ACS), those with nonfunctioning adrenal incidentalomas (NFAIs), and control subjects without adrenal tumors.MethodsA cross-sectional study was performed, incluidng the following 3 groups: patients with ACS (cortisol post–dexamethasone suppression test [DST] >1.8 μg/dL), NFAIs (cortisol post-DST ≤ 1.8 μg/dL), and patients without adrenal tumors (control group). Patients of the 3 groups were matched according to age (±5 years), sex, and body mass index (±5 kg/m²). Body composition was evaluated by bioelectrical impedance and abdominal computed tomography (CT) and urinary steroid profile by gas chromatography mass spectrometry.ResultsThis study enrolled 25 patients with ACS, 24 with NFAIs, and 24 control subjects. Based on CT images, a weak positive correlation between the serum cortisol level post-DST and subcutaneous fat area (r = 0.3, P =.048) was found. As assessed by bioelectrical impedance, lean mass and bone mass were positively correlated with the excretion of total androgens (r = 0.56, P <.001; and r = 0.58, P <.001, respectively); visceral mass was positively correlated with the excretion of glucocorticoid metabolites and total glucocorticoids (r = 0.28, P =.031; and r = 0.42, P =.001, respectively). Based on CT imaging evaluation, a positive correlation was observed between lean mass and androgen metabolites (r = 0.30, P =.036) and between visceral fat area, total fat area, and visceral/total fat area ratio and the excretion of glucocorticoid metabolites (r = 0.34, P =.014; r = 0.29, P =.042; and r = 0.31, P =.170, respectively).ConclusionThe urinary steroid profile observed in adrenal tumors, comprising a low excretion of androgen metabolites and high excretion of glucocorticoid metabolites, is associated with a lower lean mass and bone mass and higher level of visceral mass in patients with adrenal tumors.     

Clinical and Radiological Features of Pheochromocytoma/Ganglioneuroma Composite Tumors: A Case Series with Comparative Analysis

ObjectiveTo describe and compare the clinical, biochemical, radiologic, and pathologic features of adrenal pheochromocytoma-ganglioneuroma (PC-GN) composites with the features of isolated pheochromocytomas (PCs) and adrenal ganglioneuromas (AGNs).MethodsWe reviewed data for PC-GN composite cases seen at a single tertiary center between 1993 and 2012 and compared them with cases of isolated AGN and relatively similar median-size PCs.ResultsNine PC-GN composites were included. The median age at diagnosis was 52 years (range, 28 to 83 years) for PC-GN compared with 55 years (range, 24 to 78 years) for PC patients and 40 years (range, 18 to 64 years) for AGN patients. Similar to PCs, all PC-GN composites were associated with catecholamine overproduction, whereas AGNs were nonfunctioning. On pathology, the median tumor sizes were 7 cm (range, 2.5 to 13 cm) for PC-GN tumors, 6.5 cm (range, 3.5 to 7 cm) for PCs, and 8 cm (range, 3.2 to 20 cm) for AGNs. On computed tomography (CT) imaging, PC-GN composites and PCs were heterogeneous, with both having significantly higher postcontrast density values than AGNs, which typically looked homogeneous and had a progressive enhancement pattern without contrast washout in most cases.ConclusionThe presence of a PC component significantly increases tumor heterogeneity and postcontrast density values. CT imaging could be very helpful in distinguishing AGNs from both PC-GN and PC tumors, but only pathologic examination can yield the diagnosis. Clinically and radiologically, PC-GN composites are indistinguishable from PCs and need to be managed similarly. (Endocr Pract. 2014;20:864-869)     

Prognostic Value of Components of Body Composition in Patients Treated with Targeted Therapy for Advanced Renal Cell Carcinoma: A Retrospective Case Series

BackgroundTo evaluate the association between various components of body composition and overall survival of patients treated with targeted therapies for advanced renal cell carcinoma.MethodsThis retrospective study included 124 Chinese patients with advanced renal cell carcinoma who had been treated with targeted therapy from 2008 to 2012 at Fudan University Cancer Center. The L3 plane from a computed tomography scan was analyzed. Area and density were recorded as quantitative and quality measures. Univariate and multivariate Cox proportion hazard regression models were constructed to calculate the crude and adjusted hazard ratio (HR) of various components of body composition for overall survival. X-tile software was used to search for optimal cutoffs for male and female patients and the concordance index evaluated incremental changes in prognostication.ResultsAfter adjusting for age, sex and Heng risk stratification, only visceral adipose tissue index (HR 0.981, p = 0.002) and subcutaneous adipose tissue index (HR 0.987, p = 0.048) were independently associated with overall survival. Visceral adipose tissue remained a significant prognostic factor (HR 0.997, p = 0.005) when the influence of body mass index was included. Using defined cutoffs, patients with low VAT had double the death rate (p = 0.007). Visceral adipose tissue also added significant benefit to Heng risk stratification. Further exploratory analysis revealed that visceral adipose tissue may be an indicator of nutritional status in patients with advanced renal cell carcinoma.ConclusionRadiologic measurement of VAT is an independent prognostic factor for Asian patients treated with targeted therapy for advanced renal cell carcinoma.     

PTCH1 Gene Mutations in Keratocystic Odontogenic Tumors: A Study of 43 Chinese Patients and a Systematic Review

Background

The keratocystic odontogenic tumor (KCOT) is a locally aggressive cystic jaw lesion that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). PTCH1, the gene responsible for NBCCS, may play an important role in sporadic KCOTs. In this study, we analyzed and compared the distribution pattern of PTCH1 mutations in patients with sporadic and NBCCS-associated KCOTs.

Methods

We detected PTCH1 mutations in 14 patients with NBCCS-associated KCOTs and 29 patients with sporadic KCOTs by direct sequencing. In addition, five electronic databases were searched for studies detecting PTCH1 mutations in individuals with NBCCS-associated or sporadic KCOTs, published between January 1996 and June 2013 in English language.

Results

We identified 15 mutations in 11 cases with NBCCS-associated KCOTs and 19 mutations in 13 cases with sporadic KCOTs. In addition, a total of 204 PTCH1 mutations (187 mutations from 210 cases with NBCCS-associated and 17 mutations from 57 cases with sporadic KCOTs) were compiled from 78 published papers.

Conclusions

Our study indicates that mutations in transmembrane 2 (TM2) are closely related to the development of sporadic KCOTs. Moreover, for the early diagnosis of NBCCS, a genetic analysis of the PTCH1 gene should be included in the new diagnostic criteria.     

Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain

Many ion channel genes have been associated with human genetic pain disorders. Here we report two large Chinese families with autosomal-dominant episodic pain. We performed a genome-wide linkage scan with microsatellite markers after excluding mutations in three known genes (SCN9A, SCN10A, and TRPA1) that cause similar pain syndrome to our findings, and we mapped the genetic locus to a 7.81 Mb region on chromosome 3p22.3–p21.32. By using whole-exome sequencing followed by conventional Sanger sequencing, we identified two missense mutations in the gene encoding voltage-gated sodium channel Na_v1.9 (SCN11A): c.673C>T (p.Arg225Cys) and c.2423C>G (p.Ala808Gly) (one in each family). Each mutation showed a perfect cosegregation with the pain phenotype in the corresponding family, and neither of them was detected in 1,021 normal individuals. Both missense mutations were predicted to change a highly conserved amino acid residue of the human Na_v1.9 channel. We expressed the two SCN11A mutants in mouse dorsal root ganglion (DRG) neurons and showed that both mutations enhanced the channel’s electrical activities and induced hyperexcitablity of DRG neurons. Taken together, our results suggest that gain-of-function mutations in SCN11A can be causative of an autosomal-dominant episodic pain disorder.     

Management Of Catecholamine-Secreting Tumors In Pregnancy: A Review

Objective: Catecholamine-secreting tumors (pheochromocytomas and paragangliomas) presenting during pregnancy are extremely rare, but they can be fatal to both mother and fetus. Recent discoveries in the genetic background of these tumors are expected to address an increasing number of at-risk women to prenatal diagnosis.Methods: The literature was reviewed in order to provide clinicians with a practical and updated guide on how to manage this life-threatening condition.Results: The clinical presentation of catecholamine-secreting tumors can be deceptive and mimic common disorders of pregnancy. Silent catecholamine-secreting tumors can become evident during pregnancy, and hypertension cannot be considered a hallmark for this condition: some women may be normotensive or develop orthostatic hypotension. Biochemical screening includes measurement of plasma free metanephrines or urinary fractioned metanephrines. Measurement of catecholamines, dopamine, and methoxytyramine can provide further information on tumor biology, location, and prognosis. Diagnostic imaging is limited, and medical treatment requires a cautious balance between hemodynamic control and effects on the fetoplacental unit. Several genes have been associated with syndromes including catecholamine-secreting tumors, and positive genetic testing can correlate with tumor behavior. Timing and modalities for tumor removal and delivery, including anesthetic management, depend on gestational age, maternal and fetal wellbeing, control of catecholamine excess, suspicion of multiple or malignant disease, and surgical accessibility to the tumor.Conclusion: A timely diagnosis and a multidisciplinary approach are the keys to improve pregnancy outcomes in patients with a catecholamine-secreting tumor; each case should be managed in a tertiary referral center.Abbreviations:CCB = calcium channel blockerCST = catecholamine-secreting tumorMRI = magnetic resonance imagingPG = paragangliomaPHEO = pheochromocytoma     

Acute Sirolimus Overdose: A Multicenter Case Series

BackgroundThere are few data relating to sirolimus overdose in the medical literature. Our objectives were to describe all cases of overdose with sirolimus reported to Swiss, German and Austrian Poisons Centres between 2002-2013.MethodsAn observational case-series analysis was performed to determine circumstances, magnitude, management and outcome of sirolimus overdose.ResultsFive cases of acute sirolimus overdose were reported – three in young children and two in adults. Four were accidental and one was with suicidal intent. Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening. Serial blood concentration measurements were performed starting 24 h after ingestion of 103 mg in a single case, and these followed a similar pharmacokinetic time-course to measurements taken after dosing in the therapeutic range.ConclusionsAcute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated, however children might be at greater risk of developing complications. Further study of sirolimus overdose is needed.     

Hypoxia Increases the Cyclic AMP Content of the Cat Carotid Body In Vitro

The cyclic AMP content of cat carotid bodies in vitro measured with a radioimmunoassay under control conditions (PO2: 230 torr) was 0.79 +/- 0.10 pmol/carotid body (n = 10). Lowering medium PO2 to 20 torr for 2 min significantly increased cyclic AMP content to 1.13 +/- 0.14 pmol/carotid body (n = 10). This increase was inhibited neither by propranolol (34 microM) nor by propranolol plus haloperidol (27 microM). Inhibition of the cyclic nucleotide phosphodiesterase with 1-methyl-3-isobutylxanthine (0.8 mM) provoked a fast and large increase in cyclic AMP during both control and hypoxic conditions. The cyclic AMP increase induced by hypoxia was still observed when extracellular Ca2+ was absent. Inhibition of the adenylate cyclase by N-(cis-2-phenylcyclopentyl)azacyclotridecan-2-imine hydrochloride (MDL 12330A; 20-1,000 microM) under zero-Ca2+ conditions irreversibly inhibited the cyclic AMP increase produced by hypoxia. Similarly, inhibition of the Ca2(+)-calmodulin complex by trifluoperazine (0.2 mM) or calmidazolium (R 24571; 50-200 microM) prevented the cyclic AMP response. These results suggest that cyclic AMP may be involved in the PO2-sensing mechanism of the carotid body. Hypoxia appears to activate adenylate cyclase directly and independent of any hormone-receptor interactions.     

Impression Cytology In Patients With Keratoconjunctivitis Sicca

Impression cytology is a simple and painless procedure that allows the collection of the superficial layers of the conjunctival epithelium. Each sample is assigned a grade of epithelial metaplasia, and goblet cell density is calculated in each one. We have studied the superior and temporal bulbar conjuctiva of dry eyes and have compared it with that of normal controls. In normal and dry eyes we find a statistically significant difference both in goblet cell density and grade of metaplasia, between superior and temporal bulbar conjunctiva. the differences in grade of metaplasia and goblet cell density between normal and dry eyes are significant in the superior conjunctiva, but in the temporal conjunctiva we only find significant differences in grade of metaplasia.     

A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations

Background

Telomerase is an enzyme specialized in maintaining telomere lengths in highly proliferative cells. Loss-of-function mutations cause critical telomere shortening and are associated with the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia and with idiopathic pulmonary fibrosis. Here, we sought to determine the spectrum of clinical manifestations associated with telomerase loss-of-function mutations.

Methodology/Principal Findings

Sixty-nine individuals from five unrelated families with a variety of hematologic, hepatic, and autoimmune disorders were screened for telomerase complex gene mutations; leukocyte telomere length was measured by flow fluorescence in situ hybridization in mutation carriers and some non-carriers; the effects of the identified mutations on telomerase activity were determined; and genetic and clinical data were correlated. In six generations of a large family, a loss-of-function mutation in the telomerase enzyme gene TERT associated with severe telomere shortening and a range of hematologic manifestations, from macrocytosis to acute myeloid leukemia, with severe liver diseases marked by fibrosis and inflammation, and one case of idiopathic pulmonary fibrosis but not with autoimmune disorders. Additionally, we identified four unrelated families in which loss-of-function TERC or TERT gene mutations tracked with marrow failure, pulmonary fibrosis, and a spectrum of liver disorders.

Conclusions/Significance

These results indicate that heterozygous telomerase loss-of-function mutations associate with but are not determinant of a large spectrum of hematologic and liver abnormalities, with the latter sometimes occurring in the absence of marrow failure. Our findings, along with the link between pulmonary fibrosis and telomerase mutations, also suggest a common pathogenic mechanism for fibrotic diseases in which defective telomere repair plays important role.     

Practical Role of Mutation Analysis for Imatinib Treatment in Patients With Advanced Gastrointestinal Stromal Tumors: A Meta-Analysis

Background

Imatinib has become the standard first line treatment of gastrointestinal stromal tumors (GIST) in the advanced phase and adjuvant setting. We carried out an up-to-date meta-analysis to determine the practical role of mutation analysis for imatinib treatment in patients with advanced GIST.

Methods

Eligible studies were limited to imatinib treatment for patients with advanced GIST and reported on mutation analysis. Statistical analyses were conducted to calculate the odds ratio (OR), hazard ratio (HR) and 95% confidence interval (CI) using fixed-effects and random-effects models.

Results

A total of 2834 patients from 3 randomized controlled trials and 12 cohort studies were included. The ORs of response rates in KIT exon 11-mutant GISTs were 3.504 (95% CI 2.549-4.816, p<0.001) and 3.521 (95% CI 1.731-7.165, p=0.001) compared with KIT exon 9-mutant and wild type GISTs, respectively. The HRs of progression-free survival in KIT exon 11-mutant GISTs were 0.365 (95% CI 0.301-0.444, p<0.001) and 0.375 (95% CI 0.270-0.519, p<0.001) compared with KIT exon 9-mutant and wild type GISTs. The HRs of overall survival in KIT exon 11-mutant GISTs were 0.388 (95% CI 0.293-0.515, p<0.001) and 0.400 (95% CI 0.297-0.538, p<0.001) compared with KIT exon 9-mutant and wild type GISTs. No statistical significant differences were found between KIT exon 9-mutant and wild type. The overall response rate in KIT-exon 11-mutant GISTs were 70.5% (65%-75.9%) compared with 57.1% (51%-63.2%) in KIT-positive GISTs. No evidence of publication bias was observed.

Conclusion

Patients with advanced GIST harboring a KIT exon 11 mutation have the best response rate and long-term survival with imatinib treatment. Mutation analysis would be more helpful than KIT expression analysis to decide appropriate therapy for a specific patient.     

Hyperglycemia Management In Patients With Posttransplantation Diabetes

Objective: Posttransplantation diabetes (PTDM) is a common occurrence after solid-organ transplantation and is associated with increased morbidity, mortality, and health care costs. There is a limited number of studies addressing strategies for hyperglycemia management in this population, with a few articles emerging recently.Methods: We performed a PubMed search of studies published in English addressing hyperglycemia management of PTDM/new-onset diabetes after transplant (NODAT). Relevant cited articles were also retrieved.Results: Most of the 25 publications eligible for review were retrospective studies. Insulin therapy during the early posttransplantation period showed promise in preventing PTDM development. Thiazolidinediones have been mostly shown to exert glycemic control in retrospective studies, at the expense of weight gain and fluid retention. Evidence with metformin, sulfonylureas, and meglitinides is very limited. Incretins have shown promising results in small prospective studies using sitagliptin, linaglitpin, and vildagliptin and a case series using liraglutide.Conclusion: Prospective randomized studies assessing the management of hyperglycemia in PTDM are urgently needed. In the meantime, clinicians need to be aware of the high risk of PTDM and associated complications and current concepts in management.Abbreviations:A1c = glycated hemoglobin A1cCHF = congestive heart failureCNI = calcineurin inhibitorsCS = corticosteroidsDM = diabetes mellitusDPP-4 = dipeptidyl peptidase-4GLP-1 = glucagon-like peptide-1ICU = intensive care unitIGT = impaired glucose toleranceNODAT = new-onset diabetes after transplantationOGTT = oral glucose tolerance testPTDM = posttransplantation diabetesSU = sulfonylureaT2DM = type 2 diabetes mellitusTZD = thiazolidinedione     

Biochemical Characterization of P4-ATPase Mutations Identified in Patients with Progressive Familial Intrahepatic Cholestasis

Mutations in the P4-ATPase ATP8B1 cause the inherited liver disease progressive familial intrahepatic cholestasis. Several of these mutations are located in conserved regions of the transmembrane domain associated with substrate binding and transport. Assays for P4-ATPase-mediated transport in living yeast cells were developed and used to characterize the specificity and kinetic parameters of this transport. Progressive familial intrahepatic cholestasis mutations were introduced into the yeast plasma membrane P4-ATPase Dnf2p, and the effect of these mutations on its catalysis of phospholipid transport were determined. The results of these measurements have implications for the basis of the disease and for the mechanism of phospholipid transit through the enzyme during the reaction cycle.     

GTP Cyclohydrolase I and Tyrosine Hydroxylase Gene Mutations in Familial and Sporadic Dopa-Responsive Dystonia Patients

Dopa-responsive dystonia (DRD) is a rare inherited dystonia that responds very well to levodopa treatment. Genetic mutations of GTP cyclohydrolase I (GCH1) or tyrosine hydroxylase (TH) are disease-causing mutations in DRD. To evaluate the genotype-phenotype correlations and diagnostic values of GCH1 and TH mutation screening in DRD patients, we carried out a combined study of familial and sporadic cases in Chinese Han subjects. We collected 23 subjects, 8 patients with DRD, 5 unaffected family members, and 10 sporadic cases. We used PCR to sequence all exons and splicing sites of the GCH1 and TH genes. Three novel heterozygous GCH1 mutations (Tyr75Cys, Ala98Val, and Ile135Thr) were identified in three DRD pedigrees. We failed to identify any GCH1 or TH mutation in two affected sisters. Three symptom-free male GCH1 mutation carriers were found in two DRD pedigrees. For those DRD siblings that shared the same GCH1 mutation, symptoms and age of onset varied. In 10 sporadic cases, only two heterozygous TH mutations (Ser19Cys and Gly397Arg) were found in two subjects with unknown pathogenicity. No GCH1 and TH mutation was found in 40 unrelated normal Han Chinese controls. GCH1 mutation is the main etiology of familial DRD. Three novel GCH1 mutations were identified in this study. Genetic heterogeneity and incomplete penetrance were quite common in DRD patients, especially in sporadic cases. Genetic screening may help establish the diagnosis of DRD; however, a negative GCH1 and TH mutation test would not exclude the diagnosis.