Carotid body tumors are not associated with an increased risk for sleep-disordered breathing.

PURPOSE: Tumors in the carotid bodies may interfere with their function as peripheral chemoreceptors. An altered control of ventilation may predispose to sleep-disordered breathing. This study aimed to assess whether patients with unilateral or bilateral carotid body tumors (uCBT or bCBT, respectively) or bilateral CBT resection (bCBR) display sleep-disordered breathing and to evaluate the global contribution of the peripheral chemoreceptor to the hypercapnic ventilatory response. METHODS: Eight uCBT, eight bCBT, and nine bCBR patients and matched controls underwent polysomnography. The peripheral chemoreflex drive was assessed using euoxic and hyperoxic CO2 rebreathing tests. Daytime sleepiness and fatigue were assessed with the Epworth Sleepiness Scale and the Multidimensional Fatigue Index. RESULTS: All patient groups reported significant fatigue-related complaints, but no differences in excessive daytime sleepiness (EDS) were found. The apnea/hypopnea index (AHI) did not differ significantly between patient groups and controls. Only in bCBT patients, a trend towards a higher AHI was observed, but this did not reach significance (p=0.06). No differences in the peripheral chemoreflex drive were found between patients and controls. CONCLUSIONS: Patients with (resection of) CBTs have more complaints of fatigue but are not at risk for EDS. The presence or resection of CBTs is neither associated with an altered peripheral chemoreflex drive nor with sleep-disordered breathing.

Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites.

CONTEXT: A substantial number of patients with head and neck paragangliomas (HNPGLs) have biochemically active tumors, evidenced by increased urinary excretion of catecholamines and metabolites, including 3-methoxytyramine (3MT). It is unclear whether plasma levels of these parameters are more sensitive to detect biochemical activity in HNPGL patients than urinary excretion rates. OBJECTIVE: To compare plasma free levels vs urinary excretion rates of deconjugated 3MT and combined metanephrines (MNs) in patients with HNPGL. PATIENTS AND METHODS: We included 124 consecutive patients with HNPGL for screening of catecholamine excess by measurement of 24-h urinary excretion rates of deconjugated (nor)metanephrine, (nor)epinephrine, dopamine, vanillylmandelic acid, 3MT, and plasma free levels of (nor)metanephrine and 3MT. RESULTS: Plasma free 3MT levels were increased in 35 of the 124 patients (28%), whereas 24-h urinary excretion of deconjugated 3MT was increased in 30 patients (24%) (P=0.13). Plasma free MN levels were increased in seven patients (6%) and urinary deconjugated MN levels in six patients (5%) (P=1.00). Plasma free normetanephrine (NMN) levels were increased in seven patients (6%), and five patients had increased urinary excretion of deconjugated NMN (4%) (P=0.69). Plasma free combined MN levels (NMN, MN, and 3MT) were increased in 41 patients (33%), whereas 24-h urinary excretion rates of deconjugated combined MNs were increased in 33 patients (27%, P<0.05). CONCLUSIONS: The combined levels of free MNs and free 3MT in plasma indicate a higher number of biochemically active HNPGLs than the 24-h urinary excretion rates of these markers.

High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.

Mutations in four genes encoding subunits or cofactors of succinate dehydrogenase (SDH) cause hereditary paraganglioma and pheochromocytoma syndromes. Mutations in SDHB and SDHD are generally the most common, whereas mutations in SDHC and SDHAF2 are far less frequently observed. A total of 1045 DNA samples from Dutch paraganglioma and pheochromocytoma patients and their relatives were analyzed for mutations of SDHB, SDHC, SDHD or SDHAF2. Mutations in these genes were identified in 690 cases, 239 of which were index cases. The vast majority of mutation carriers had a mutation in SDHD (87.1%). The second most commonly affected gene was SDHAF2 (6.7%). Mutations in SDHB were found in only 5.9% of samples, whereas SDHC mutations were found in 0.3% of samples. Remarkably, 69.1% of all carriers of a mutation in an SDH gene in the Netherlands can be attributed to a single founder mutation in SDHD, c.274G>T and p.Asp92Tyr. Moreover, 88.8% of all SDH mutation carriers carry one of just six Dutch founder mutations in SDHB, SDHD and SDHAF2. The dominance of SDHD mutations is unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. In addition, we found that most SDH mutation-related paragangliomas-pheochromocytomas in the Netherlands can be explained by only six founder mutations in SDHAF2, SDHB and SDHD. The findings underline the regional differences in the SDH mutation spectrum, differences that should be taken into account in the development of effective screening protocols. The results show the crucial role that demographic factors play in the frequency of gene mutations.

Patients previously treated for nonfunctioning pituitary macroadenomas have disturbed sleep characteristics, circadian movement rhythm, and subjective sleep quality.

CONTEXT AND OBJECTIVE: Fatigue and excessive sleepiness have been reported after treatment of nonfunctioning pituitary macroadenomas (NFMA). Because these complaints may be caused by disturbed nocturnal sleep, we evaluated objective sleep characteristics in patients treated for NFMA. DESIGN: We conducted a controlled cross-sectional study. SUBJECTS AND METHODS: We studied 17 patients (8 women; mean age, 54 yr) in remission of NFMA during long-term follow-up (8 yr; range, 1-18 yr) after surgery (n = 17) and additional radiotherapy (n = 5) without comorbidity except for hypopituitarism and 17 controls matched for age, gender, and body mass index. Sleep was assessed by nocturnal polysomnography, sleep and diurnal movement patterns by actigraphy, and quality of life and subjective sleep characteristics by questionnaires. RESULTS: Compared to controls, patients had reduced sleep efficiency, less rapid eye movement sleep, more N1 sleep, and more awakenings in the absence of excessive apnea or periodic limb movements. Actigraphy revealed a longer sleep duration and profound disturbances in diurnal movement patterns, with more awakenings at night and less activity during the day. Patients scored higher on fatigue and reported impaired quality of life. CONCLUSION: Patients previously treated for NFMA suffer from decreased subjective sleep quality, disturbed distribution of sleep stages, and disturbed circadian movement rhythm. These observations indicate that altered sleep characteristics may be a factor contributing to impaired quality of life and increased fatigue in patients treated for NFMA.

Pheochromocytomas detected by biochemical screening in predisposed subjects are associated with lower prevalence of clinical and biochemical manifestations and smaller tumors than pheochromocytomas detected by signs and symptoms.

CONTEXT: Sporadic pheochromocytomas are detected by clinical signs and symptoms, whereas pheochromocytomas in patients with a known hereditary predisposition for these tumors are detected by repetitive screening for catecholamine excess. OBJECTIVE: To document the clinical, biochemical, and pathological differences between patients with sporadic pheochromocytomas, detected by signs and symptoms and patients with pheochromocytomas, detected by biochemical screening in established hereditary syndromes. DESIGN: Retrospective follow-up study. PATIENTS AND METHODS: We included 60 consecutive patients diagnosed with pheochromocytoma (pheochromocytomas detected by signs and symptoms: n=28 and pheochromocytomas detected by screening: n=32) in our center. RESULTS: Patients with pheochromocytomas detected by screening presented with less complaints of diaphoresis (P<0.01), palpitations (P=0.01), paleness (P=0.01), nausea (P<0.01), and vomiting (P=0.01) compared with patients with symptomatic pheochromocytomas. Patients with pheochromocytomas detected by screening tended to be younger at the time of diagnosis (41+/-2 vs 47+/-3 years, P=0.07). In addition, patients with pheochromocytomas detected by screening had significantly lower rates of 24-h urinary catecholamine excretion, and considerably smaller tumors (3.7+/-0.5 vs 7.3+/-0.7 cm, P<0.01). CONCLUSIONS: Pheochromocytomas detected by screening of patients with a hereditary predisposition have a much lower prevalence of signs and symptoms, lower catecholamine excess, and smaller tumors, compared with sporadic pheochromocytomas, detected by signs and symptoms. These data support the benefits of screening for pheochromocytomas in patients with hereditary syndromes predisposing for these tumors.

Increased urinary excretion of 3-methoxytyramine in patients with head and neck paragangliomas.

CONTEXT: Patients with head-and-neck paragangliomas (HNPGL) are regularly screened for catecholamine excess. The clinical relevance of increased urinary secretion of 3-methoxytyramine is unclear in HNPGL. OBJECTIVE: The aim of the study was to assess the prevalence and the clinical, biochemical, and radiological presentation of patients with HNPGL with increased urinary excretion of 3-methoxytyramine. PATIENTS AND METHODS: A total of 136 consecutive patients with HNPGL were included and screened for catecholamine excess by measurement of 24-h urinary excretion of (nor)metanephrine, (nor)epinephrine, vanillylic mandelic acid, dopamine, and 3-methoxytyramine. In patients with catecholamine excess, abdominal/intrathoracic paragangliomas were excluded by (123)I-metaiodobenzylguanidine scintigraphy, magnetic resonance imaging, and/or computed tomography. RESULTS: Urinary 3-methoxytyramine excretion was increased in 31 of the 136 patients (23%). In 18 of these 31 patients, this was the only sign of biochemical activity of HNPGL. Dopamine excretion was higher in subjects with increased 3-methoxytyramine excretion (1.62 +/- 0.1 micromol/24 h vs. 2.5 +/- 0.3 micromol/24 h; P < 0.01). Of the 136 HNPGL patients, 21 (15%) had excessive excretion of at least one catecholamine and/or their metabolites when 3-methoxytyramine excretion was not taken into account. With the inclusion of patients with excessive 3-methoxytyramine excretion, 39 (29%) had excessive catecholamine excretion. Patients with 3-methoxytyramine excess had significantly more complaints of palpitations (P < 0.01), diaphoresis (P = 0.03), collapse (P < 0.05), and a higher pulse rate (P < 0.01). Increased excretion of 3-methoxytyramine was not associated with particular types of HNPGL or genotypes. CONCLUSIONS: A substantial number of HNPGL patients have biochemically active tumors, reflected in increased excretion of 3-methoxytyramine, associated with increased dopamine excretion. Some patients only display increased excretion of 3-methoxytyramine, but not of other catecholamines or their metabolites.

High prevalence of arthropathy, according to the definitions of radiological and clinical osteoarthritis, in patients with long-term cure of acromegaly: a case-control study.

OBJECTIVE: To evaluate the prevalence and rheumatological and radiological characteristics of arthropathy in patients after long-term cure of acromegaly in comparison with age-matched controls. DESIGN: Case-control study. PATIENTS: We compared 89 patients with adequate biochemical control of acromegaly (mean 14 years) and 67 age-matched controls. MEASUREMENTS: Study parameters were the results of symptom questionnaires, structured physical examination and radiographs of the spine, hip, knee and hand. The diagnosis of osteoarthritis was based on a) radiological osteoarthritis determined by Kellgren and Lawrence and b) clinical osteoarthritis determined by the American College of Rheumatology (ACR) criteria. For the radiological comparison with controls, a Dutch reference group was used. RESULTS: Pain/stiffness at > or =1 joint site was reported by 72% of patients, most frequently in the spine and hands. Radiological osteoarthritis at > or =1 joint site was present in 99% of patients, most frequently in the spine and hip, and increased at all joint sites in comparison with controls (odds ratios: 2-20). Despite long-term cure of acromegaly, the characteristic widening of joint spaces was still present. In addition, severe osteophytosis was present. Representative radiographs of these typical features are included in the manuscript. According to the ACR criteria, clinical osteoarthritis at > or =1 joint site was present in 63% of patients, most frequently in the spine and hand. Patients had a higher prevalence of osteoarthritis than controls at all joint sites according to all scoring methods and at a younger age. CONCLUSIONS: Prior GH excess has irreversible, deleterious late effects on the clinical and radiological aspects of joints in patients with long-term cure of acromegaly.