[A rare case of diencephalic cachexia in an adult female with cranio-pharyngioma]. / Redkii sluchai razvitiia diéntsefal'noi kakheksii u vzrosloi zhenshchiny s kraniofaringiomoi.

Diencephalic cachexia (DС) is progressive weight loss despite a normal caloric intake and a satisfactory state of health, which is caused by hypothalamic lesions. This is a rare (about 100 cases were reported) and potentially fatal disorder of unknown pathogenesis. At present, there is no effective pharmacological therapy for the disorder. Cachexia may regress only if the tumor reduces in size, therefore the timely diagnosis and treatment are of vital importance for the patient. DС is typical of early childhood, and only a few cases have been reported in adults. We present a rare case of DС in a 24-year-old female with papillary craniopharyngioma.

Neuropsychological outcome in patients with childhood craniopharyngioma and hypothalamic involvement.

OBJECTIVE: To test memory performance and executive functions in patients with childhood craniopharyngioma and hypothalamic involvement. STUDY DESIGN: Using standardized neuropsychological tests, we compared cognitive performance in a group of 15 patients with childhood craniopharyngioma and known hypothalamic involvement and a group of 24 age- and intelligence-matched control subjects. In addition, we compared individual patients' results with normative data to detect abnormal performance in the clinically relevant range. Within the patient group, we further tested whether the grade of hypothalamic involvement had an impact on cognitive performance and quality of life. RESULTS: Relative to healthy controls, the patients demonstrated significantly lower performance scores in tests of memory and executive functioning. On the individual performance level, delayed recall performance was severely impaired in one-third of the patients. Compared with patients with low-grade hypothalamic involvement, those with high-grade hypothalamic involvement showed worse performance in executive functions and reduced functional capabilities for daily life actions, indicating lower quality of life. CONCLUSION: Our findings demonstrate that hypothalamic involvement is related to impairments in memory and executive functioning in patients with childhood craniopharyngioma and indicate that a high grade of hypothalamic involvement is related to worse outcomes.

Endocrine dysfunction in Taiwanese children with human chorionic gonadotropin-secreting germ cell tumors.

BACKGROUND/PURPOSE: Human chorionic gonadotropin (HCG)-secreting germ cell tumors (GCTs) are rare childhood malignancies with unique clinical manifestations but delayed diagnosis is common. The purpose of this study is to investigate the clinical manifestations and endocrine dysfunction of Taiwanese children with HCG-secreting GCTs. METHODS: From 1991 to 2011, 24 children (19 boys and five girls) with HCG-secreting GCTs were evaluated for their clinical findings and endocrine functions. RESULTS: The mean age at diagnosis of the study patients was 10.8 ± 3.1 years. Of the 24 patients, 20 had central nervous system (CNS) GCTs and four had primary mediastinal GCTs (PMGCTs). The most common pathologic findings were germinomas and mixed type GCTs. The common initial symptoms and signs included polyuria, polydipsia, rapid growth, neurologic deficit,sexual precocity, and growth retardation. There was a delay in diagnosis in about 60% of patients. Diabetes insipidus and hypopituitarism were common endocrine dysfunctions in patients with CNSGCTs. Twelve boys had gonadotropin-independent puberty upon diagnosis, which were related to their high serum ß-hCG levels. None of the five girls had this disorder despite their high serum ß-hCG levels. Three of the four PMGCTs patients had the classic form of Klinefelter syndrome. CONCLUSION: Taiwanese children with HCG-secreting GCTs often have clinical manifestations related to endocrine dysfunction. High index of suspicion is important to avoid delayed diagnosis in these children.

Paroxysmal tonic eye deviation: an atypical presentation of hypothalamic hamartoma.

Hypothalamic hamartoma is a rare developmental non-neoplastic malformation, often characterised by early onset gelastic seizures and later progressive cognitive and behavioural deterioration. In this case study, we have examined a child who presented with an atypical onset of benign paroxysmal gaze deviation between two to three months of age. The patient subsequently developed gelastic seizures at age 13. Based on the observation that hypothalamic hamartomas do not involve any functional region involved in eye motility, we speculate that both gaze deviation and gelastic seizures are a manifestation of the epileptogenic nature of the hypothalamic hamartoma. [Published with video sequences].

The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children.

INTRODUCTION: In this study, we have investigated the role of leptin, soluble leptin receptor(sOb-R), resistin, and insulin secretory dynamics in the development of hypothalamic obesity. MATERIALS AND METHODS: Children who had hypothalamo-pituitary tumor were divided into two groups. First group included obese-overweight (hypothalamic obese = HOB group, n = 23) and second group included non-obese children (hypothalamic non-obese = HNOB group, n = 16). Exogenously obese-overweight children (OB group, n = 22) were included as controls. Basal and second-hour serum glucose and insulin in oral glucose tolerance test (OGTT), basal serum leptin, sOb-R, resistin levels, and homeostasis model assessment (HOMA) indexes were compared between the groups. RESULTS: Age, sex, and pubertal status were similar in study groups. Median and interquartile ranges of body mass index (BMI) z scores were similar in HOB and OB groups (2.0 (1.5-2.1) and 2.1 (1.8-2.3), respectively). Serum leptin levels corrected for BMI were highest and total leptin/sOb-R ratios (free leptin index (FLI)) tended to be higher in HOB than HNOB and OB groups, indicating leptin resistance (leptin/BMI, 4.0 (1.6-5.2), 1.5 (0.8-3.1), and 2.5 (1.8-3.5); FLI, 2.0 (0.8-3.5), 0.6 (0.3-1.2), and 1.5 (1-2.3) in HOB, HNOB, and OB groups; respectively). Serum resistin levels were similar in groups (2.6 (1.9-3.1), 2.8 (1.7-3.4), and 3.0 (2.2-3.5) ng/ml in HOB, HNOB, and OB groups, respectively). Basal serum glucose, basal and second-hour insulin levels in OGTT, and HOMA index were higher in OB group than the HOB and HNOB groups, indicating insulin resistance in simple obesity; however, increment of insulin to same glycemic load in OGTT was highest in the HOB group indicating insulin dysregulation (p < 0.05). CONCLUSION: Hypothalamic obesity seems to be related to both dysregulated afferent (leptin) and efferent (insulin) neural outputs through the autonomic nervous system resulting in energy storage as fat.

Eating behaviour and oxytocin in patients with childhood-onset craniopharyngioma and different grades of hypothalamic involvement.

BACKGROUND: Patients with childhood-onset craniopharyngioma (CP) often suffer from tumour or treatment-related hypothalamic lesions (HL). These lesions may alter production of oxytocin, which plays a major role in the regulation of eating behaviour and body composition. OBJECTIVE: In CP with different degrees of HL, we investigated associations between HL, eating behaviour/eating attitudes, and oxytocin saliva concentrations (OSC). METHODS: In a cross-sectional case-control study on 34 CP and 73 healthy controls, OSC were measured before, and 60 minutes after breakfast by immunoassay. Eating behaviour, attitudes, and habits were assessed by standardized questionnaires. RESULTS: CP with anterior + posterior HL presented with more adverse eating behaviours/symptoms of eating disorders than CP without HL, CP with anterior HL, and controls. Eating behaviour in CP with anterior HL was similar to controls, except for their tendency towards high dietary restraints. Decreases in postprandial compared with fasting OSC were associated with adverse eating behaviour in CP and controls and with higher BMI in CP. CONCLUSIONS: CP with anterior HL and CP with anterior + posterior HL present with distinct patterns of eating behaviour. Reduced postprandial compared with fasting OSC is associated with weight problems in CP and with adverse eating behaviour and symptoms of eating disorders in both CP and controls.

Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man.

The first half of this manuscript is devoted to a review of the methods used and the results obtained in the published measurements of the normal responses to tests of the three main types of hypothalamic-pituitary-adrenocortical (HPA) activity in man. These are, I, basal, unstressed activity leading to appropriate levels of total daily production of cortisol in the characteristic circadian pattern; II, responses to feedback stimulation of HPA activity by metyrapone administration; and III, responses to tests of the effects of stress on the HPA system including the effects of hypoglycemia, induced fever, vasopressin administration, and ACTH injections and infusions. The advantages and shortcomings of each type of procedure are discussed. The second half of this paper describes the authors' attempts to establish the limits of normality of standard and modified methods of evaluating the HPA system. The defined limits of normality have been used to assess the HPA function in 158 patients with known or suspected disorders of the HPA system. In normal controls, halfhourly plasma cortisol determinations established the normality of circadian and postprandial fluctuations and of mean plasma cortisol concentration, 6.2 +/- 0.3 (SEM) micrograms/dl, which were closely approximated by determinations every 6 h. Metyrapone, given in a dose of 500 mg every 2 h for 24 h increased urinary 17-OHCS excretion to 10.5-32.6 mg/day or to 1.7-7.8 times basal excretion rate. Increasing rates of insulin infusion disclosed significant relationships between resulting plasma glucose and cortisol concentrations. The slopes of the delta cortisol/delta glucose responses were similar after insulin infusions (0.46 +/- 0.05) and after insulin injections, 0.15 U/kg (0.43 +/- 0.09), and were always greater than 0.20 micrograms/mg. This index provides a useful objective measure of the normality of responses to hypoglycemic stress, 0.20-0.87 micrograms/mg. Adrenocortical responses to iv infusions of ACTH (cosyntropin 0.25 mg) may be equivocal at 2 h but are clear cut at 4, 6 and 8 h. Of 158 patients in whom hypopituitarism was known or suspected because of the presence of a pituitary tumor, acromegaly, hyperprolactinemia, or clinical features, HPA function was found to be entirely normal in 88 patients and partially or severely abnormal in the remaining 70 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of hypothalamopituitary axis dysfunction of intrasellar and third ventricular craniopharyngiomas in children.

In this study, we attempted to determine if different locations of a tumor influence the hypothalamopituitary axis function and outcomes with childhood craniopharyngiomas. The preoperative, postoperative, and long-term follow-up endocrinological disturbances of 66 children with a craniopharyngioma were retrospectively studied. The patients were divided into two subgroups according to the location of the tumor (intrasellar and third ventricle floor). The mean age at onset was 8.02 (range, 1.42-17.58)years. These patients were followed-up for a median duration of 7.2 (range, 2-22)years. Vision problems as the first symptom were more common in Group One (with intrasellar tumors) compared to Group Two (55.6% vs 15.4%; p=0.001; Fisher's exact test). Increased intracranial pressure was the most common initial symptom in patients in Group Two (51.3%) and the second most common symptom in Group One (37%). The majority of patients in both Group One and Group Two required some forms of pituitary hormone supplements (96% vs 84%). At the last follow-up, more patients with intrasellar craniopharyngiomas needed cortisone supplements (79.2% in Group One vs 45.9% in Group Two; p=0.016; Fisher's exact test); however, children with third ventricle floor tumors had more prevalent weight gain (4.2% in Group One vs 27.0% in Group Two; p=0.038; Fisher's exact test). There were different initial presentations and endocrinological outcomes between children with intrasellar and third ventricle floor craniopharyngiomas. The intrasellar tumors had greater pituitary hormone disturbance. However, at the long-term follow-up, children with third ventricle floor tumors had a greater prevalence of being overweight and obese, which was associated with hypothalamic dysfunction.

Paired overexpression of ErbB3 and Sox10 in pilocytic astrocytoma.

Pilocytic astrocytoma (PA) is the most common glioma of childhood. Despite their relatively high incidence, the molecular mechanisms responsible for tumorigenesis and growth of PA are poorly understood. Previous in vitro studies in our laboratory showed that despite the absence of ErbB1, PA was sensitive to ErbB1 tyrosine kinase inhibitor gefitinib. To identify alternative targets of gefitinib in PA, we studied other members of the ErbB receptor tyrosine kinase family that have been identified in brain tumors. Using gene expression microarray and Western blot analyses, we found that ErbB3 is highly overexpressed in PA compared with other pediatric brain tumors (glioblastoma, ependymoma, medulloblastoma, atypical teratoid/rhabdoid tumor, and choroid plexus papilloma). Developmental biology studies have identified Sox10 as a regulator of ErbB3 expression during development of the neural crest. Investigation of Sox10 in PA revealed that it is highly overexpressed relative to other pediatric brain tumors, lending support to the theory that Sox10-regulated overexpression of ErbB3 may be driving growth in PA. Sox10-regulated ErbB3 overexpression is a novel insight into the biology of PA, suggests possible recapitulation of developmental pathways in tumorigenesis, and presents possible targets for therapeutic intervention that might be used for hypothalamic variants not amenable to surgical cure.

Is there a role for ghrelin and peptide-YY in the pathogenesis of obesity in adults with acquired structural hypothalamic damage?

CONTEXT: Obesity is a common sequel to hypothalamic tumors and their treatment, but the underlying mechanisms are not fully established. OBJECTIVE: Our objective was to evaluate the role of ghrelin and peptide-YY (PYY) in human hypothalamic obesity. SETTING: The study took place at a University Medical Center. PARTICIPANTS: Subjects included 14 adult patients (six male, eight female) with tumors of the hypothalamic region and 15 healthy controls (six male and nine female) matched for age, body mass index, and percentage of body fat. INTERVENTIONS: Plasma ghrelin and total PYY were measured using RIAs after an overnight fast and 15, 30, 60, 120, and 180 min after a mixed meal. MAIN OUTCOME MEASURES: We assessed ghrelin, PYY, and appetite ratings. RESULTS: The fall in ghrelin levels after the test meal was similar in the two groups. There was no statistically significant change postprandially in circulating PYY in the patients with hypothalamic damage. Fasting leptin levels and postprandial insulin responses were also similar in the two groups. Patients with hypothalamic damage reported higher hunger ratings at 3 h after the meal (P = 0.01) and a stronger desire to eat at 2 h (P = 0.01) and 3 h (P = 0.02) compared with the control group. CONCLUSIONS: Adult patients with structural hypothalamic damage show impaired satiety, but the changes observed in circulating ghrelin and PYY concentrations in response to a test meal do not indicate a central role for these gut hormones in the control of appetite and the pathogenesis of obesity in these patients.

Melatonin secretion and increased daytime sleepiness in childhood craniopharyngioma patients.

Craniopharyngioma is a rare dysontogenetic benign tumor. Patients frequently suffer from endocrine deficiencies, sleep disturbances, and obesity due to pituitary and hypothalamic lesions. A self-assessment daytime sleepiness questionnaire (German version of the Epworth Sleepiness Scale) was used to evaluate 79 patients with childhood craniopharyngioma. Because hypothalamic lesions may explain daytime sleepiness in craniopharyngioma patients, salivary melatonin and cortisol concentrations were examined in obese and nonobese craniopharyngioma patients (n = 79), patients with hypothalamic pilocytic astrocytoma (n = 19), and control subjects (n = 30). Using a general linear model procedure analyzing the influence of body mass index (BMI) and tumor diagnosis on diurnal salivary melatonin, we found that morning salivary melatonin levels were related to BMI (by F test, P = 0.004) and tumor diagnosis (by F test, P = 0.032). Also for nighttime salivary melatonin levels significant relations with BMI (by F test, P < 0.001) and tumor diagnosis (by F test, P = 0.025) were detectable. Melatonin concentrations in saliva of craniopharyngioma patients collected at night or in the morning showed a negative correlation (night: Spearman's rho = -0.42; P = 0.001; morning: Spearman's rho = -0.31; P = 0.020) with the patient's Epworth Sleepiness Scale score. Severely obese craniopharyngioma patients and severely obese hypothalamic tumor patients had similar patterns of melatonin secretion. Differences in terms of diurnal salivary cortisol concentrations were not detectable when patient groups and controls were compared. We speculate that hypothalamic lesions might be responsible for both obesity and daytime sleepiness. As decreased nocturnal melatonin levels were associated with increased daytime sleepiness, BMI, and hypothalamic tumor diagnosis, further studies on the beneficial effects of melatonin substitution on daytime sleepiness and weight control in these patients are warranted.

Hypothalamic obesity in humans: what do we know and what can be done?

Obesity is a common sequel to tumours of the hypothalamic region and their treatment with surgery and radiotherapy. The prevalence of hypothalamic obesity has been underestimated because it may take some years to develop, and the problem has been under-recognized by physicians. Weight gain results from damage to the ventromedial hypothalamus which leads, variously, to hyperphagia, a low metabolic rate, autonomic imbalance, growth hormone (GH) deficiency and various other problems that contribute to weight gain. However, with the exception of GH replacement, few clinical trials have evaluated significant numbers of patients and so the roles of various behavioural, dietary, pharmacological and obesity surgery approaches are controversial. Sufficient knowledge exists to identify those at high risk of hypothalamic obesity so that weight gain prevention approaches can be offered. In those who are already obese, we propose that the principal causal mechanisms in individual patients should be considered as a basis for guiding clinical management.

Pallister-Hall syndrome associated with an unbalanced chromosome translocation.

We report 3 cases of Pallister-Hall syndrome involving hypothalamic hamartoblastoma, hypopituitarism, cranial, and limb abnormalities. The first 2 cases represent the first apparent sibs reported with this syndrome. Patient 1 represents the first known patient with this syndrome with an abnormal karyotype.

Growth hormone (GH) responses to the combined administration of GH-releasing hormone plus GH-releasing peptide 6 in adults with GH deficiency.

In recent years the health problems of adults with growth hormone deficiency (GHD) and the benefits of GH replacement therapy have received considerable attention. However, the reliability of conventional GH tests in the assessment of pituitary GH reserve in this group of patients is still controversial. In this study, we assessed GH secretion after the combined administration of GH-releasing hormone (GHRH) (1 microgram/kg iv) and GH-releasing peptide 6 (GHRP-6, 1 microgram/kg iv) in adult patients diagnosed with GHD by conventional GH testing, and correlate this response with insulin-like growth factor I levels. Twenty-one subjects (13 male, 8 female) with long-standing diagnosis of GHD aged 21-54 years were studied. In 13 subjects GH responses to GHRH plus GHRP-6 were markedly reduced (peak GH response < 10 mU/l), whereas in the remaining eight the response was greater (range 11-100 mU/l). In conclusion, our data show that combined administration of GHRH plus GHRP-6 elicited a significant increase in plasma GH levels in about 40% of patients diagnosed with GHD by conventional GH testing.

Neurologic manifestations of hypothalamic disease.

The hypothalamus, in addition to regulating the anterior and posterior pituitary, controls water balance through thirst, regulates food ingestion and body temperature, influences consciousness, sleep, emotion and other behaviors. Much has been learned of these effects in human disease through the clinical manifestations that occur with hypothalamic lesions. This study reviews the clinical pathologic correlations that have been made in recent years showing that regions of the hypothalamus exert functions in humans that are similar to those identified in experimental animals. Clinical pathologic correlations have not always provided precise analysis of hypothalamic function. The hypothalamus is small and often lesions that come to clinical attention achieve considerable size before their recognition, making local anatomic dissections of the effects of the lesions difficult. Nevertheless, the use of modern non-invasive techniques including CT scans and magnetic resonance imaging (MRI) have provided new information not previously available. This paper reviews several cases of hypothalamic disorder recognized recently. (1) A 33-year-old black man with hypothalamic sarcoidosis. Manifestations of hypothalamic dysfunction included panhypopituitarism, aggressive hyperphagia, polydipsia (partially due to hyperglycemia secondary to diabetes mellitus), drowsiness, depression, and irritability. (2) A 37-year-old woman with a large intrahypothalamic tumor (biopsy showed pituitary adenoma), with drowsiness, poikilothermia, lack of satiety, confusion, and memory loss. She becomes depressed when she is transiently more alert (as after hypertonic contrast-dye infusion). (3) A 60-year-old man with hypothalamic compression by a pituitary tumor, associated with syndrome of inappropriate ADH (SIADH), severe anorexia, memory loss, but preserved thirst. After surgical decompression of the tumor his appetite acutely recovered, but he developed severe hypo(poikilo)thermia. (4) A 45-year-old woman with a suprasellar craniopharyngioma presented with severe drowsiness, hyperphagia, depression, and memory loss post-operatively, which responded to antidepressants (except for the memory loss). She had extremely labile blood pressures and serum Na for about 1 week post-operatively.

A discrete lesion of ventral hypothalamus and optic chiasm that disturbed the daily temperature rhythm.

A patient with a discrete metastasis in the ventral hypothalamus and optic chiasm is reported, who developed an abnormal daily rhythm of oral temperature without alteration of the 24-h mean temperature. This region, its afferents, and its efferents appear to be important in the neural regulation of human circadian rhythmicity.

Hypothalamic dysfunction and symptoms of anorexia nervosa.

It is clinically well recognized that certain symptoms in anorexia nervosa such as motor hyperactivity, alert and animated mental disposition, and insufficient awareness of bodily changes are inconsistent with profound emaciation. This article discusses the metabolic, endocrine-hypothalamic, and neurotransmitter changes that occur in anorexia nervosa and explores the relationship of these changes to the development and maintenance of these symptoms.

Impaired temporal context memory on anterograde but not retrograde tests in the absence of frontal pathology.

This study examined the memory performance of patient RK who developed substantial memory impairments due to a hypothalamic glioma but in the absence of any evidence of frontal disturbance. RK was evaluated on both tests of anterograde and retrograde memory for temporal context. In the first experiment he exhibited marked deficits on a list discrimination task even when recognition performance was well within control range. Experiment 2 confirmed this disproportionate impairment of temporal order memory and showed that RK's list discrimination deficit was as severe as that found in alcoholic Wernicke-Korsakoff Syndrome patients. Experiment 3 showed that RK's temporal discrimination deficit was not a general deficit in discrimination because he performed normally on a spatial discrimination test of comparable difficulty to the temporal task. Experiment 4 examined RK's memory for deceased famous people and his ability to indicate the half decade in which they died. RK's performance was indistinguishable from controls whereas WKS patients were extremely impaired. This study adds to the view that frontal damage is not a necessary condition for impairment on anterograde measures of temporal context memory. However, further evidence from this study indicates that temporal judgments about pre-existing memories may depend on intact frontal lobe functioning.

Multiple system Erdheim-Chester disease with massive hypothalamic-sellar involvement and hypopituitarism.

Erdheim-Chester disease (ECD) is a rare multiple system histiocytosis that is characterized pathologically by xanthogranulomatous infiltrates and radiologically by symmetrical sclerosis of long bones. The diagnosis is often confirmed by biopsy of bone or of orbital or retroperitoneal soft tissue. Intracranial involvement is rare. The authors report a case of ECD in which the diagnosis was made after biopsy of a hypothalamic mass. The mass had been discovered during a workup for panhypopituitarism in a 55-year-old man with urological and bone disease. Aside from diabetes insipidus, other features of pituitary insufficiency have seldom been reported and no patients have presented with a hypothalamic tumor. The endocrinological and neurological aspects of ECD are discussed, as is its differential diagnosis. Reported cases of the disorder associated with hypopituitarism or found during biopsy of central nervous system structures are also reviewed.