Body mass index at diagnosis of a childhood brain tumor; a reflection of hypothalamic-pituitary dysfunction or lifestyle?

PURPOSE: Childhood brain tumor survivors (CBTS) are at risk of becoming overweight, which has been shown to be associated with hypothalamic-pituitary (HP) dysfunction during follow-up. Body mass index (BMI) at diagnosis is related to BMI at follow-up. It is uncertain, however, whether aberrant BMI at brain tumor diagnosis reflects early hypothalamic dysfunction or rather reflects genetic and sociodemographic characteristics. We aimed to examine whether BMI at childhood brain tumor diagnosis is associated with HP dysfunction at diagnosis or its development during follow-up. METHODS: The association of BMI at diagnosis of a childhood brain tumor to HP dysfunction at diagnosis or during follow-up was examined in a Dutch cohort of 685 CBTS, excluding children with craniopharyngioma or a pituitary tumor. Individual patient data were retrospectively extracted from patient charts. RESULTS: Of 685 CTBS, 4.7% were underweight, 14.2% were overweight, and 3.8% were obese at diagnosis. Being overweight or obese at diagnosis was not associated with anterior pituitary deficiency or diabetes insipidus at diagnosis or during follow-up. In children with suprasellar tumors, being obese at diagnosis was associated with central precocious puberty. CONCLUSION: Overweight or obesity at diagnosis of a childhood brain tumor seems not to be associated with pituitary deficiencies. These results suggest that genetics and lifestyle may be more important etiologic factors for higher BMI at diagnosis in these children than hypothalamic dysfunction. To improve the long-term outcome of CBTS with regards to overweight and obesity, more attention should be given to lifestyle already at the time of brain tumor treatment.

Neuropsychiatric profile of paediatric hypothalamic hamartoma: systematic review and case series.

AIM: To evaluate neuropsychiatric comorbidities in children and adolescents with hypothalamic hamartoma. METHOD: We retrospectively analysed case notes for all individuals with hypothalamic hamartoma referred to Great Ormond Street Hospital, London, between 2000 and 2016. In addition, a systematic review aiming to identify all previous paediatric case series was performed. Psychiatric symptoms, demographics, physical comorbidities, and cognitive functioning were recorded for all cases where possible. Analyses were performed to determine which factors were associated with psychopathology and potential mechanisms investigated. RESULTS: Forty-six cases were included in the case series (28 males, 18 females; mean age at assessment 11y 8mo [1y 11mo-16y 11mo, SD 4y 0mo]). Twenty-nine papers representing data from 264 cases met inclusion criteria for the systematic review. Overall, at least 50% of cases presented with psychopathology. Epilepsy, intellectual disability, and male sex were associated with externalizing disorders (attention-deficit/hyperactivity disorder, conduct and oppositional defiance disorders, and rage attacks). Intellectual disability mediated the effects of epilepsy on externalizing psychopathology. No factors were associated with internalizing disorders (anxiety and depressive disorders), although these were not well reported. INTERPRETATION: Psychiatric comorbidities are highly prevalent in the presentation of paediatric hypothalamic hamartoma. The aetiology of psychopathology comprises a range of interacting biological and psychosocial factors with particular influence from epilepsy. Further research is required to achieve an evidence base for treatment. WHAT THIS PAPER ADDS: Over half of children with hypothalamic hamartoma present with psychiatric comorbidity. Externalizing and internalizing disorders are present in approximately 60% and 30% of children with hypothalamic hamartomas respectively. Epilepsy and male sex are associated with externalizing psychopathology. Intellectual disability mediates the association between epilepsy and externalizing symptoms. No clear associations are evident for internalizing disorders or precocious puberty.

PERFIL NEUROPSIQUIÁTRICO DEL HAMARTOMA HIPOTALÁMICO EN PEDIATRÍA: REVISIÓN SISTEMÁTICA Y SERIE DE CASOS: OBJETIVO: Evaluar las comorbilidades neuropsiquiátricas en niños y adolescentes con hamartoma hipotalámico. MÉTODO: En este estudio analizamos retrospectivamente las notas de los casos de todos los individuos con hamartoma hipotalámicos referidos al Great Ormond Street Hospital, London, entre el 2000 y 2016. Además, realizamos una revisión bibliográfica sistemática dirigida a identificar la serie de casos pediátricos. Síntomas psiquiátricos, demográfico, comorbilidades físicas y funcionamiento cognitivo fueron recolectados en todos los casos posibles.Se efectuaron análisis para determinar qué factores se asociaron con psicopatología y se investigaron mecanismos potenciales. RESULTADOS: En total 46 casos fueron incluidos en la serie de casos (28 masculinos, 18 femeninos, media de edad a la evaluación 11 años y 8 meses, DS 4 años y 0 mes). La revisión bibliográfica identifico 29 artículos describiendo 264 casos que reunieron criterios de inclusión para la extracción de datos. En total, al menos 50% de casos presentaban psicopatología. Epilepsia, discapacidad intelectual, y sexo masculino fueron asociados con desórdenes externos (déficit de atención con hiperactividad, desórdenes conductuales y oposicional desafiante, ataques de furia). Ningún factor fue asociado con la internalización de desórdenes neuropsiquiátricos (desórdenes de ansiedad y depresión), aunque éstos no fueron bien reportados. INTERPRETACIÓN: Las comorbilidades psiquiátricas son altamente prevalentes en la presentación del hamartoma hipotalámico pediátrico. La etiología de la psicopatología comprende un rango de interacciones biológicas y factores psicosociales con particular influencia de la epilepsia. Se requiere más información de investigación para reunir evidencia científica que guie el tratamiento.

PERFIL NEUROPSIQUIÁTRICO DO HAMARTOMA HIPOTALÂMICO PEDIÁTRICO: REVISÃO SISTEMÁTICA E SÉRIE DE CASOS: OBJETIVO: Avaliar comorbidades neuropsiquiátricas em crianças e adolescentes com hamartoma hipotalâmico. MÉTODO: Nós analisamos retrospectivamente os registros de casos de todos os indivíduos encaminhados para o Hospital Great Ormond Street, Londres, entre 2000 e 2016. Além disso, uma revisão sistemática visando identificar todos os casos pediátricos prévios foi realizada. Sintomas psiquiátricos, dados demográficos, comorbidades físicas, e funcionamento cognitivo foram registrados para todos os casos em que foi possível. Análises foram realizadas para determinar quais fatores se associavam com psicopatologia e potenciais mecanismos foram investigados. RESULTADOS: Quarenta e seis casos foram incluídos na série de casos (28 do sexo masculino, 18 do sexo feminino; média de idade na avaliação 11a 8m (1a 11m-16a 11m, DP 4a 0m). Vinte e nove artigos representando dados de 264 casos atenderam aos critérios de inclusão para a revisão sistemática. No total, pelo menos 50% dos casos apresentaram psicopatologia. Epilepsia, deficiência intelectual, e sexo masculino eram associados com desordens externalizantes (transtorno de déficit de atenção e hiperatividade, transtornos de conduta e de desafio oposicional, e ataques de raiva). A deficiência intelectual mediou os efeitos da epilepsia e da psicopatologia externalizante. Nenhum fator foi associado com transtornos internalizantes (ansiedade e transtornos depressivos), embora estes não tenham sido bem reportados. INTERPRETAÇÃO: Comorbidades psiquiátricas são altamente prevalentes na apresentação do hamartoma hipotalâmico pediátrico. A etiologia da psicopatologia envolve uma variedade de fatores biológicos e psicossociais que interagem, com particular influência da epilepsia. Mais pesquisas são necessárias para se atingir uma base de evidências para o tratamento.

Psychiatric comorbidity with hypothalamic hamartoma: Systematic review for predictive clinical features.

OBJECTIVE: We conducted a systematic review of the English-language literature to identify clinical features associated with a higher risk of psychiatric symptoms (aggression and rage behaviors) in patients with hypothalamic hamartoma (HH) and epilepsy. METHODS: Two publicly-accessible databases (PubMed and Cochrane Library) were searched for Hypothalamic Hamartoma AND Epilepsy. We identified peer-reviewed original research publications (case reports or clinical series; N=19) in which clinical data was provided on an individual basis. Subjects were cohorted into those with (N=51) and without (N=68) behavioral aggression. Multiple clinical features were collated and subjected to univariate analysis to determine possible differences between these two cohorts. RESULTS: The presence of aggression significantly correlated with 1) male gender, 2) younger age at time of first seizure onset, 3) the presence of intellectual disability, and 4) the presence of multiple seizure types (versus gelastic seizures only). For those patients undergoing surgical treatment, aggression also correlated with younger age at the time of surgical intervention. CONCLUSION: Possible predictive clinical features for the presence of aggression and rage behaviors in patients with hypothalamic hamartoma and epilepsy are identified. These results may contribute to the complex treatment decisions that are unique to this population.

[Evolution of ideas and techniques, and future prospects in epilepsy surgery]. / Évolution des idées et des techniques, et perspectives d'avenir en chirurgie de l'épilepsie.

INTRODUCTION: The aim of this article was to review and evaluate the published literature related to the outcome of epilepsy surgery, while placing it in an historical perspective, and to describe the future prospects in this field. STATE OF ART: Temporal lobe surgery achieves seizure freedom in about 70% of cases. Seizure outcome is similar in the pediatric population. Extratemporal resections impart good results to 40% to 60% of patients, with a better prognosis in the case of frontal lobe surgery. Pediatric hemispherotomy leads to seizure control in about 80% of children. Radiosurgery used as a treatment for temporal mesial epilepsy has an outcome quite similar to that obtained with surgical resection, but provides a neuropsychological advantage. Radiosurgery is also effective in 60% of children treated for seizures related to hypothalamic hamartoma. Regarding palliative surgery, callosotomy and multiple subpial transections show satisfactory outcomes in over 60% of cases. Neuromodulation techniques (vagus nerve stimulation and bilateral stimulation of the anterior nucleus of the thalamus) allow a 50% reduction of seizures in half of patients. PERSPECTIVES: Transcranial magnetic stimulation combined with electroencephalography seems a promising technique because of its diagnostic, prognostic and therapeutic applications. Transcranial ultrasound stimulation, which can reversibly control neuronal activity, is also under consideration. Concerning neuromodulation, trigeminal nerve stimulation may become an alternative to vagus nerve stimulation; while other targets of deep brain stimulation are being evaluated. Also, the possibility of coupling SEEG seizure focus detection with concomitant laser or radiofrequency focus destruction is under development. CONCLUSIONS: Constant evolution of epilepsy surgery has improved patient outcomes over time. Current research and development axes suggest the continuation of this trend and a reduction of the invasiveness of surgical procedures.

Functional hypothalamic amenorrhea and its influence on women's health.

INTRODUCTION: Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea. There are three types of FHA: weight loss-related, stress-related, and exercise-related amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). The final consequences are complex hormonal changes manifested by profound hypoestrogenism. Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 (IGF-1) and low total triiodothyronine. AIM: The aim of this work is to review the available data concerning the effects of FHA on different aspects of women's health. RESULTS: Functional hypothalamic amenorrhea is related to profound impairment of reproductive functions including anovulation and infertility. Women's health in this disorder is disturbed in several aspects including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of FHA. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. FHA patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects. CONCLUSIONS: FHA patients should be carefully diagnosed and properly managed to prevent both short- and long-term medical consequences.

Comparison of body composition, basal metabolic rate and metabolic outcomes of adults with Prader Willi syndrome or lesional hypothalamic disease, with primary obesity.

CONTEXT: The care of patients with hypothalamic obesity is challenging. OBJECTIVE: To compare body composition, basal metabolic rate (BMR) and metabolic outcomes of adults, with lesional or genetic hypothalamic obesity, with obese patients suffering from primary obesity, once matched for body mass index (BMI). DESIGN AND PATIENTS: Adults with hypothalamic obesity of genetic origin (Prader Willi syndrome (PWS)) or acquired hypothalamic damage (HD), such as craniopharygioma, were compared with obese control candidates awaiting bariatric surgery (C), with a BMI between 35 and 65 kg m(-)(2), and aged between 18 and 50 years. MAIN OUTCOME MEASURES: Body composition measured by whole-body dual-energy X-ray absorptiometry scanning, BMR using indirect calorimetry, hormonal and metabolic assessments. RESULTS: A total of 27 adults with a genetic diagnosis of PWS, 15 obese subjects with HD and 206 obese controls with similar BMI were studied. Compared with the control group, PWS patients had an increased percentage of fat mass (FM), and a decreased percentage of android FM. The BMR of PWS patients was significantly lower than controls and highly correlated with lean body mass in PWS and C patients. Body composition of HD was similar with those of obese patients. A trend toward an increased prevalence of diabetes in HD patients and of cytolysis in PWS was observed in comparison with primary obese patients. CONCLUSION: Genetic and lesional hypothalamic obesities have different consequences for phenotypic features such as body composition or BMR compared with primary obese patients. The mechanisms of adipose tissue development and metabolic complications may be different between genetic and lesional obesities.

High prevalence of fibromyalgia-associated symptoms in patients with hypothalamic-pituitary disorders.

OBJECTIVES: Various complaints of patients with fibromyalgia often resemble clinical features observed in patients with hypothalamic-pituitary diseases. The aim of this study was to evaluate whether patients with hypothalamic-pituitary diseases are at increased risk for fibromyalgia syndrome (FMS). METHODS: A questionnaire for evaluating fibromyalgia-associated symptoms was sent to 121 patients with hypothalamic-pituitary disorders (HPD) (60 women, 61 men; mean age, 55.4 years; range, 21-83 years) of the endocrine outpatient clinic. 115 patients (57 women, 58 men; mean age 56.9 years; range, 21 to 82 years) with cardiovascular diseases (CD) served as controls. RESULTS: Fibromyalgia-associated symptoms regarding muscular complaints were significantly more frequent in the HPD group than in CD patients (53.7 % vs. 35.7%, p= 0.003). In particular, we found a significant higher prevalence of autonomic symptoms in the HPD group as compared to the CD group regarding several qualities (cold hands, p=0.039; flatulence, p=0.022; tiredness, p=0.017). In addition, swollen and painful finger joints were reported more often in the HPD group than in the CD group (p=0.002). Of note, no differences regarding any fibromyalgia-associated symptom were detected when patients with hypothalamic-pituitary hormone excess syndromes were compared to those with a pituitary pathology without hormonal excess. Similarly, prevalence of fibromyalgia-associated symptoms was not related to the treatment modality of pituitary disease; i.e. surgical vs. conservative or any hormonal replacement therapy. CONCLUSIONS: Our data suggest that patients with hypothalamic-pituitary disorders may be at increased risk of developing fibromyalgia-associated symptoms.

[Hypothalamic hamartoma in paediatric patients: clinical characteristics, outcomes and review of the literature]. / Hamartoma hipotalámico en la edad pediátrica: características clínicas, evolución y revisión de la literatura.

OBJECTIVE: To describe the epidemiological and clinical-electroencephalographic characteristics, and associated morbidity of patients with hypothalamic hamartoma, as well as the treatment followed and outcomes PATIENTS AND METHODS: We have retrospectively reviewed the medical histories of 10 patients diagnosed with hypothalamic hamartoma by magnetic resonance imaging over the last 20 years. RESULTS: The age of onset of epilepsy in patients with hypothalamic hamartoma in our series was between the first days of life and 2 years. Of the 10 total patients, 8 had epileptic seizures during its progress. All of them had gelastic seizures, in addition to other types of seizures, with the most common being partial simple seizures. The electroencephalographic findings recorded were highly variable. One of the patients developed epileptic encephalopathy. Five patients had some kind of conduct disorder. Five patients had cognitive problems. At least 2 different antiepileptic drugs were measured in 8 of the patients who had seizures, and in 6 of these some type of non-pharmacological treatment had been used with the objective of seizure control. Only in 3 of 8 patients has been achieved Acceptable control of epilepsy had only been achieved in 3 out the 8 patients. Five patients of the series developed precocious puberty. The average time of follow-up of the series was approximately 6 years. CONCLUSIONS: Epilepsy is the most frequent manifestation of hypothalamic hamartomas. Most cases were drug-resistant, which led to difficulties in the management of these patients, requiring surgery for their control on many occasions. Psychiatric comorbidity and cognitive impairment is common.

Morphometry of the pituitary gland and hypothalamus in long-term survivors of childhood trauma.

PURPOSE: Chronic pituitary dysfunction is increasingly recognized as a sequela of traumatic brain injury (TBI). Our aim was to rule out any late morphometric changes of the pituitary gland and hypothalamus in survivors of TBI during childhood requiring intensive care. METHODS: We assessed morphometric abnormalities of the sella region and hypothalamus in patients who sustained TBI during childhood. The patients showed no clinical hormonal dysfunction at the acute phase and pituitary hormone levels at the time of our study were within normal limits. From the 18 enrolled patients in the magnetic resonance study, five were removed due to morphological changes or anatomical variations. We studied the MRI of 13 male survivors (mean age 27 years, mean time after trauma 20 years) and compared them to 13 male control subjects who were matched in terms of age (mean age, 26 years), education and ethnicity. Analyses of the pituitary gland and sella on a midsagittal T2- and T1-weighted image were performed. We used voxel-based morphometry (VBM), an unbiased MRI morphometric method to investigate hypothalamic region in this group of patients. RESULTS: There was only a trend towards a reduced pituitary gland width in the patient group compared to controls. However, no significant morphological and morphometric abnormality was seen and VBM showed no hypothalamic grey matter loss. CONCLUSION: In the absence of hormonal dysfunction, no persisting morphometric changes of the pituitary gland and hypothalamus were seen in survivors of childhood TBI requiring intensive care.

Hypothalamic-pituitary dysfunction in alternating hemiplegia of childhood.

BACKGROUND: Many central nervous system disorders result in hypothalamic-pituitary (HP) axis dysfunction. Alternating Hemiplegia of Childhood (AHC) is usually caused by mutations in the ATP1A3 subunit of the Na+/K+ ATPase, predominantly affecting GABAergic interneurons. GABAergic interneurons and the ATP1A3 subunit are both important for function of the hypothalamus. However, whether HP dysfunction occurs in AHC and, if so, how such dysfunction manifests remains to be investigated. METHODS: We conducted a retrospective review of a cohort of 50 consecutive AHC patients for occurrence of HP related manifestations and analyzed the findings of the 6 patients, from that cohort, with such manifestations. RESULTS: Six out of 50 AHC patients manifested HP dysfunction. Three of these patients were mutation positive and 3 were mutation negative. Of the 6 patients with HP dysfunction, 3 had central precocious puberty. A fourth had short stature due to growth hormone deficiency. Two other patients had recurrent episodes of fever of unknown origin (FUO) diagnosed, after workups, as being secondary to central fever. All patients were evaluated and co-managed by pediatric neurology and endocrinology or rheumatology. CONCLUSION: AHC was associated with HP dysfunction in about 12% of patients. Awareness of such dysfunction is important for anticipatory guidance and management particularly in the case of FUO which often presents a diagnostic dilemma. Our findings are also consistent with current understandings of the underlying pathophysiology of AHC and of the HP axis.

Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

CONTEXT: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). OBJECTIVE: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. METHODS: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. RESULTS: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ±â€…1.2 years in girls and 7.1 ±â€…1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ±â€…1.6 vs 1.6 ±â€…1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ±â€…1.8 vs 1.1 ±â€…1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. CONCLUSION: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.

CONTEXT: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. OBJECTIVE: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. DESIGN: We compared patients with HA to control women. SETTING: The study was conducted at secondary referral centers. PATIENTS AND OTHER PARTICIPANTS: Women with HA (n = 106) and control women (ClinSeq study; n = 468). INTERVENTIONS: We performed exome sequencing in all patients and controls. MAIN OUTCOME MEASURE(S): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. RESULTS: RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). CONCLUSIONS: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.

Prevalence and risk factors of hypothalamic-pituitary dysfunction in infant and toddler childhood brain tumor survivors.

OBJECTIVE: Childhood brain tumor survivors (CBTS) are at risk to develop hypothalamic-pituitary (HP) dysfunction (HPD). The risk for HPD may vary between different age groups due to maturation of the brain and differences in oncologic treatment protocols. Specific studies on HPD in infant brain tumor survivors (infant-BTS, 0-1 years at diagnosis) or toddler brain tumor survivors (toddler-BTS, ≥1-3 years) have not been performed. PATIENTS AND METHODS: A retrospective nationwide cohort study in CBTS was performed. Prevalence and risk factors for HPD were compared between infant-, toddler-, and older-BTS. Subgroup analysis was performed for all non-irradiated CBTS (n = 460). RESULTS: In total, 718 CBTS were included, with a median follow-up time of 7.9 years. Overall, despite the less frequent use of radiotherapy (RT) in infants, no differences in the prevalence of HPD were found between the three groups. RT (OR: 16.44; 95% CI: 8.93-30.27), suprasellar tumor location (OR: 44.76; 95% CI: 19.00-105.49), and younger age (OR: 1.11; 95% CI: 1.05-1.18) were associated with HP dysfunction. Infant-BTS and toddler-BTS showed more weight gain (P < 0.0001) and smaller height SDS (P = 0.001) during follow-up. In non-irradiated CBTS, infant-BTS and toddler-BTS were significantly more frequently diagnosed with TSH-, ACTH-, and ADH deficiency, compared to older-BTS. CONCLUSION: Infant and toddler brain tumor survivors seem to be more vulnerable to develop HP dysfunction than older children. These results emphasize the importance of special infant and toddler brain tumor treatment protocols and the need for endocrine surveillance in children treated for a brain tumor at a young age.

Prevalence and clinical characteristics of isolated forms of central precocious puberty: a cohort study at a single academic center.

OBJECTIVE: Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP. DESIGN AND METHODS: This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years. RESULTS: In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance. CONCLUSION: These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

Risk Factors for Hypothalamic Obesity in Patients With Adult-Onset Craniopharyngioma: A Consecutive Series of 120 Cases.

Context: Hypothalamic obesity (HO) is a severe complication following craniopharyngioma, but studies regarding the sequelae in adult-onset patients with craniopharyngioma are sparse. Objective: The objective of the study was to describe weight changes after surgical treatment in adult-onset craniopharyngioma patients and to analyze risk factors for postoperative weight gain and HO. Subjects and Method: A retrospective analysis was conducted of 120 adult-onset patients who underwent surgery for craniopharyngioma and follow-up at the institution of the authors between January 2018 and September 2020. Clinical characteristics, anthropometric data, image features, treatment modalities, and endocrine indices were collected. Multivariable logistic regression analysis was used to identify independent risk factors for postoperative weight gain and HO. Results: Forty-nine (40.8%) patients had clinically meaningful weight gain (≥5%) in a median follow-up time of 12.0 months (range 1.0-41.0 months) after surgery. The mean postoperative weight gain in this subgroup was 17.59 ± 12.28 (%). Weight gain continued in the first year following surgery. Patients with lower preoperative BMI [OR 0.78, 95% CI (0.67-0.90), P = 0.001] and the adamantinomatous subtype [OR 3.46, 95% CI (1.02-11.76), P = 0.047] were more likely to experience postoperative weight gain ≥5%. The prevalence of HO was 19.2% preoperatively and increased to 29.2% at last follow-up postoperatively. Only preoperative BMI [OR 2.51, 95% CI (1.64-3.85), P < 0.001] was identified as an independent risk factor for postoperative HO. Conclusions: HO is a common complication in patients with adult-onset craniopharyngioma. Patients with higher preoperative BMI had a greater risk for developing HO postoperatively.

Hypothalamic-pituitary dysfunction in survivors of childhood brain tumors in Prasat Neurological Institute.

OBJECTIVE: To assess hypothalamic-pituitary dysfunction in childhood brain tumor survivors in Prasat Neurological Institute. MATERIAL AND METHOD: Between October 2007 and September 2008, 19 brain tumor survivor children in Prasat Neurological Institute without recurrence at least 2 years after complete treatment were included in the present study. The patients were categorized according to brain tumor location into directly (DHPA) (9 cases) and indirectly (IDHPA) (10 cases) involving hypothalamic-pituitary axis. All patients were treated by surgery. Furthermore, six cases were combined with radiation and chemotherapy and 10 cases were combined with radiation therapy only. Growth Hormone (GH) stimulation test by clonidine and/or L-Dopa, ACTH stimulation test and thyroid function test (TFT) were done. RESULTS: The mean age at diagnosis was 9.9 +/- 4.6 years old and the interval from diagnosis to study was 5.8 +/- 2.2 years. Seven DHPA (77%) and seven IDHPA patients (70%) had low peak GH with significant lower level in the former group (p < 0.05). Six of seven DHPA (85%) and one IDHPA patients (10%) had low response to ACTH stimulation test. All DHPA (100%) and 10% IDHPA patients had central hypothyroidism. By ACTH stimulation test in DHPA patients, hypocortisolism was detected in five and excluded in one who later stopped prednisolone after prolonged continuation. The central hypothyroidism was newly detected in two DHPA patients and replacement therapy was initiated GH deficiency (GHD) was detected by GH stimulation test in 73% of overall brain tumors. Growth hormone therapy would be considered in the appropriate GHD patients. CONCLUSION: With effective therapy and improving survival rates of brain tumor children, hypothalamic-pituitary dysfunction in either DHPA or IDHPA group should be regularly monitored to prevent further morbidity and improve quality of life.

Molecular Signature of Multisystem Cardiometabolic Stress and Its Association With Prognosis.

Importance: Cardiometabolic disease is responsible for decreased longevity and poorer cardiovascular outcomes in the modern era. Metabolite profiling provides a specific measure of global metabolic function to examine specific metabolic mechanisms and pathways of cardiometabolic disease beyond its clinical definitions. Objectives: To define a molecular basis for cardiometabolic stress and assess its association with cardiovascular prognosis. Design, Setting, and Participants: A prospective observational cohort study was conducted in a population-based setting across 2 geographically distinct centers (Boston Puerto Rican Health Study [BPRHS], an ongoing study of individuals enrolled between June 1, 2004, and October 31, 2009; and Atherosclerosis Risk in Communities [ARIC] study, whose participants were originally sampled between November 24, 1986, and February 10, 1990, and followed up through December 31, 2017). Participants in the BPRHS were 668 Puerto Rican individuals with metabolite profiling living in Massachusetts, and participants in the ARIC study were 2152 individuals with metabolite profiling and long-term follow-up for mortality and cardiovascular outcomes. Statistical analysis was performed from October 1, 2018, to March 13, 2020. Exposure: The primary exposure was metabolite profiles across both cohorts. Main Outcomes and Measures: Outcomes included associations with multisystem cardiometabolic stress and all-cause mortality and incident coronary heart disease (in the ARIC study). Results: Participants in the BPRHS (N = 668; 491 women; mean [SD] age, 57.0 [7.4] years; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 32.0 [6.5]) had higher prevalent cardiometabolic risk relative to those in the ARIC study (N = 2152; 599 African American individuals; 1213 women; mean [SD] age, 54.3 [5.7] years; mean [SD] body mass index, 28.0 [5.5]). Multisystem cardiometabolic stress was defined for 668 Puerto Rican individuals in the BPRHS as a multidimensional composite of hypothalamic-adrenal axis activity, sympathetic activation, blood pressure, proatherogenic dyslipidemia, insulin resistance, visceral adiposity, and inflammation. A total of 260 metabolites associated with cardiometabolic stress were identified in the BPRHS, involving known and novel pathways of cardiometabolic disease (eg, amino acid metabolism, oxidative stress, and inflammation). A parsimonious metabolite-based score associated with cardiometabolic stress in the BPRHS was subsequently created; this score was applied to shared metabolites in the ARIC study, demonstrating significant associations with coronary heart disease and all-cause mortality after multivariable adjustment at a 30-year horizon (per SD increase in metabolomic score: hazard ratio, 1.14; 95% CI, 1.00-1.31; P = .045 for coronary heart disease; and hazard ratio, 1.15; 95% CI, 1.07-1.24; P < .001 for all-cause mortality). Conclusions and Relevance: Metabolites associated with cardiometabolic stress identified known and novel pathways of cardiometabolic disease in high-risk, community-based cohorts and were associated with coronary heart disease and survival at a 30-year time horizon. These results underscore the shared molecular pathophysiology of metabolic dysfunction, cardiovascular disease, and longevity and suggest pathways for modification to improve prognosis across all linked conditions.

Craniopharyngiomas: Challenges and Controversies.

Despite its benign histopathology, the treatment of craniopharyngioma remains one of the most formidable challenges faced by skull base surgeons. The technical challenges of tackling these complex central skull base lesions are paralleled by clinical challenges related to their unique tumor biology and the often-complex decision making required. In this article, we critically appraise the most recent literature to explore the challenges and controversies surrounding the management of these lesions. The role of curative resections and the shift in the surgical paradigm toward the multidisciplinary goal-directed management approach are discussed.

Gelastic seizures: a retrospective study in five tertiary hospital centres.

This study aimed to characterize, clinically and neurophysiologically, a series of patients with gelastic seizures (GS), including both adults and children. We retrospectively collected patients with GS from epilepsy clinics of five tertiary hospital centres within a single country. Patients were selected through relatives'/caregivers' descriptions, home video and/or video-EEG monitoring. GS were identified through ictal semiology. Thirty-five patients were enrolled; 62.9% had initial GS in infancy, 14.3% in adolescence and 22.8% at adult age. Twenty-six had abnormal MRI: eight presented with hypothalamic hamartoma (HH) and 16 non-HH lesions that included different structural aetiologies and genetic, metabolic and immune aetiologies. All patients with HH had their first GS in infancy or adolescence. For the remaining aetiologies, GS started in infancy in 59.3%, in adolescence in 11.1% and at adult age in 29.6%. Video-EEG data was available for analysis in 11 patients, including seven patients with a non-HH MRI lesion. The ictal onset topography on scalp video-EEG was usually concordant with the MRI lesion (in 6/7 patients) and the most frequent ictal onset was fronto-temporal. In two patients, both video-EEG and MRI suggested a parietal and occipital epileptogenic zone. Aetiologies and patterns of affected topography unrelated to HH are common in patients with GS, and all age groups may manifest with this type of ictal semiology. This ictal manifestation has no lateralizing value and, despite a clear preponderance for hypothalamic, frontal and temporal lobe origins, other brain areas, namely the parietal and occipital lobes, should be considered.

The changing burden of long-term health outcomes in survivors of childhood acute lymphoblastic leukaemia: a retrospective analysis of the St Jude Lifetime Cohort Study.

BACKGROUND: Treatment for childhood acute lymphoblastic leukemia has evolved over the past five decades, with moderation of traditional chemotherapy and radiotherapy and the introduction of targeted immune-based and cellular-based therapies. The affect of these changes on late health outcomes has not been assessed. Using data from the The St Jude Lifetime (SJLIFE) Cohort, we aimed to characterise the magnitude of morbidity and patterns of late health outcomes among survivors of childhood acute lymphoblastic leukaemia treated over time. METHODS: The St Jude Lifetime (SJLIFE) Cohort is a retrospective cohort study with prospective follow-up and ongoing data accrual designed to facilitate longitudinal, clinically-based assessment of health outcomes among survivors of paediatric malignancies. 980 survivors included in this analysis were diagnosed with paediatric acute lymphoblastic leukaemia at St Jude Children's Research Hospital (SJCRH) between Aug 28, 1963, and July 19, 2003, were aged 18 years old and older at enrolment, had a minimum follow-up of 10 years after diagnosis, and completed an initial on-campus SJLIFE assessment as of data cutoff (June 30, 2015). 272 community control participants, matched to survivors on 5-year age blocks in each sex, were recruited for comparison. Cumulative chemotherapy and radiation dose exposures and major medical events during and after therapy were retrieved from the medical records of the survivors. History or physical examination, laboratory analysis, physical fitness, and neurocognitive testing were done. Health conditions were graded according to a modified version of the Common Terminology Criteria for Adverse Events. Neurocognitive domains of attention (Trial Making Test Part A and Conner's Continuous Performance Test-II) and executive function (Trail Making Test Part B, Controlled Oral Word Association Test, and Wechsler Adult Intelligence Scale-III Digit Span Test Backward) were measured and age-adjusted Z scores were calculated. Mean cumulative count was used to calculate the age-standardised cumulative burden of health conditions over time. This cohort study is registered at ClinicalTrials.gov, number NCT00760656. FINDINGS: 980 survivors of acute lymphoblastic leukaemia (50% women, median age at diagnosis 5 years [IQR 3·1-9·1 years], and median time from diagnosis of 30·0 years [22·7-36·3]) had a median age of 35·8 years (29·4-42·9) at assessment compared with 35·1 years (28·7-42·6) for 272 controls. Survivors had significantly more growth hormone deficiency, hypogonadism, and neuropathy than controls. By age 30 years, survivors of acute lymphoblastic leukaemia had, on average, 5·4 (95% CI 5·1-5·8) grade 1-4 health conditions, including 3·2 (2·9-3·4) grade 2-4 health conditions, compared with 2·0 (CI 1·7-2·2) grade 1-4 and 1·2 (1·03-1·4) grade 2-4 health conditions among controls. The cumulative burden of grade 2-4 health conditions involved multiple organ systems for survivors treated on protocols between 1962-91, but after elimination of cranial radiotherapy for children with acute lymphoblastic leukaemia, conditions now predominately include musculoskeletal and endocrine disorders for survivors on protocols between 1991-2007. INTERPRETATION: Although changes in paediatric acute lymphoblastic leukaemia treatment protocols have improved overall survival, the burden of late morbidity remains high for these patients. We show that the pattern of late toxic effects has markedly changed over time, with survivors having a reduction in health conditions that are immediately life-threatening, however, maintaining health status and quality of life for survivors of paediatric acute lymphoblastic leukaemia requires continued medical surveillance, counselling, and lifestyle modifications. FUNDING: US National Cancer Institute and the American Lebanese Syrian Associated Charities.