Angela Maria Spinola-Castro

Detection of metabolic syndrome features among childhood cancer survivors: a target to prevent disease.

Along with the growing epidemic of obesity, the risk of atherosclerosis, cardiovascular disease morbidity, and mortality are increasing markedly. Several risk factors for cardiovascular disease, such as visceral obesity, glucose intolerance, arterial hypertension, and dyslipidemia commonly cluster together as a condition currently known as metabolic syndrome. Thus far, insulin resistance, and endothelial dysfunction are the primary events of the metabolic syndrome. Several groups have recommended clinical criteria for the diagnosis of metabolic syndrome in adults. Nonetheless, in what concerns children and adolescents, there are no unified definitions, and modified adult criteria have been suggested by many authors, despite major problems. Some pediatric disease states are at risk for premature cardiovascular disease, with clinical coronary events occurring very early in adult life. Survivors of specific pediatric cancer groups, particularly acute lymphocytic leukemia, central nervous system tumors, sarcomas, lymphomas, testicular cancer, and following bone marrow transplantation, may develop metabolic syndrome traits due to: hormonal deficiencies (growth hormone deficiency, thyroid dysfunction, and gonadal failure), drug or radiotherapy damage, endothelial impairment, physical inactivity, adipose tissue dysfunction, and/or drug-induced magnesium deficiency. In conclusion, some primary and secondary prevention remarks are proposed in order to reduce premature cardiovascular disease risk in this particular group of patients.

Adiposity in childhood cancer survivors: insights into obesity physiopathology

As childhood cancer treatment has become more effective, survival rates have improved, and a number of complications have been described while many of these patients reach adulthood. Obesity is a well-recognized late effect, and its metabolic effects may lead to cardiovascular disease. Currently, studies concerning overweight have focused on acute lymphocytic leukemia and brain tumors, since they are at risk for hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation, chemotherapy, and brain surgery) or to primary tumor location. Obesity and cancer have metabolic syndrome features in common. Thus, it remains controversial if overweight is a cause or consequence of cancer, and to date additional mechanisms involving adipose tissue and hypothalamic derangements have been considered, comprising premature adiposity rebound, hyperinsulinemia, leptin regulation, and the role of peroxisome proliferator-activated receptor gamma. Overall, further research is still necessary to better understand the relationship between adipogenesis and hypothalamic control deregulation following cancer therapy.

Turner syndrome and metabolic derangements: Another example of fetal programming

BACKGROUND AND AIM Turner syndrome (TS) patients have an increased risk of weight gain and metabolic syndrome. To date, it is unknown what factors are involved in this metabolic process, even though it is recognized that TS patients are frequently born small-for-gestational age. The aim of this study was to evaluate the correlation between lipid and glucose profiles with being overweight and birth weight and length in TS patients. STUDY DESIGN This was a cross-sectional study. SUBJECTS AND OUTCOME MEASURES Serum glucose, insulin (HOMA-IR), total cholesterol, and triglycerides were measured in 64 patients with TS. Data regarding birth weight and length and current body mass index (BMI) were also evaluated. RESULTS Total cholesterol showed a significant negative correlation with birth weight and a positive correlation with BMI; triglycerides showed significant negative correlation with birth weight and length and a positive correlation with BMI; and HOMA-IR showed a significant negative correlation with birth weight and length. Low birth weight and a high BMI were predictive for 28% of total cholesterol and triglycerides; and low birth weight for 22% of HOMA-IR. CONCLUSIONS Lipid profile was correlated with a high current BMI and low birth weight and length in TS patients and glucose profile only with low birth weight. Thus far, growth retardation may play a role in metabolic derangements in this group of patients, being considered another example of fetal programming.

The use of fluorescence in situ hybridization in the diagnosis of hidden mosaicism: apropos of three cases of sex chromosome anomalies

FISH has been used as a complement to classical cytogenetics in the detection of mosaicism in sex chromosome anomalies. The aim of this study is to describe three cases in which the final diagnosis could only be achieved by FISH. Case 1 was an 8-year-old 46,XY girl with normal female genitalia referred to our service because of short stature. FISH analysis of lymphocytes with probes for the X and Y centromeres identified a 45,X/46,X,idic(Y) constitution, and established the diagnosis of Turner syndrome. Case 2 was a 21-month-old 46,XY boy with genital ambiguity (penile hypospadias, right testis, and left streak gonad). FISH analysis of lymphocytes and buccal smear identified a 45,X/46,XY karyotype, leading to diagnosis of mixed gonadal dysgenesis. Case 3 was a 47,XYY 19-year-old boy with delayed neuromotor development, learning disabilities, psychological problems, tall stature, small testes, elevated gonadotropins, and azoospermia. FISH analysis of lymphocytes and buccal smear identified a 47,XYY/48,XXYY constitution. Cases 1 and 2 illustrate the phenotypic variability of the 45,X/46,XY mosaicism, and the importance of detection of the 45,X cell line for proper management and follow-up. In case 3, abnormal gonadal function could be explained by the 48,XXYY cell line. The use of FISH in clinical practice is particularly relevant when classical cytogenetic analysis yields normal or uncertain results in patients with features of sex chromosome aneuploidy.

Effects of growth hormone on body proportions in Turner syndrome compared with non-treated patients and normal women

Background: The majority of anthropometric assessments in Turner syndrome (TS) patients has focused on height. AIM: To analyze body proportions in young adult TS patients either treated or not treated with rhGH, and to compare them with a group of age-matched healthy women. Subjects and methods: Standing height, sitting height, weight, foot and leg lengths, arm span, head circumference, biliac and biacromial diameters were measured in 52 non-treated TS patients, 30 treated with rhGH and 133 healthy women. Results: Age at the start of rhGH therapy varied from 7.8 to 15.1 yr (10.0±1.3 yr), the duration of treatment from 2.8 to 8.2 yr (3.7±1.5 yr) and the mean recombinant human GH (rhGH) dose was 0.42 mg/kg/week (from 0.32 to 0.50 mg/kg/week). Non-treated patients did not show any difference in anthropometric variables when compared with the treated ones, except for hand length (p=0.02) and height (p=0.05), which were increased in the treated group. All anthropometric variables, except head circumference, were different when comparing TS patients (either treated or not) with age-matched healthy women. Conclusion: Brazilian TS patients either treated or not with rhGH showed almost no differences in terms of their body proportions. This result is probably due to the late age at the start of treatment, and/or the short period of rhGH administration. Hand length was different between the groups, showing the importance of including the extremities in body proportion assessment during rhGH treatment of TS patients.

Leptin assessment in acute lymphocytic leukemia survivors: role of cranial radiotherapy?

Leptin has been hypothesized to play a role in the development of obesity in leukemia survivors, particularly those who have received cranial radiotherapy. This cross-sectional study evaluated the relationship between leptin levels and body mass index (BMI) in a sample of 26 acute lymphocytic leukemia survivors of both sexes, treated with and without cranial irradiation, aged 7.6 to 17 years, at a mean 3.4±2.0 years off treatment. There were significantly more males among the irradiated group (P<0.001), even though no differences were encountered in pubertal stage (P=1.000), BMI standard deviation score (mean±SD) (0.68±1.00 vs. 1.19±0.78; P=0.164), or leptin concentrations (17.01±17.04 vs. 23.3±13.4; P=0.309). Nonetheless, there was a positive correlation between the natural logarithm of leptin and BMI standard deviation score [t(22)=2.348, P=0.028], however, no differences were recorded among irradiated and nonirradiated patients [F(2,22)=0.384, P=0.685]. When this relationship was compared between sexes, a significant difference was encountered [F(2,22)=4.907, P=0.017], with males having the strongest association (R2males=65.5%, R2females=34.7%). Leptin is a reliable adiposity index as it strongly correlates with BMI. Overall, the current data suggest that cranial irradiation did not play a role upon this relationship; however, sex differences influenced positively this correlation.

O papel do hormônio de crescimento no tratamento dos distúrbios endócrino-metabólicos do paciente com a síndrome da imunodeficiência adquirida (Aids): [revisão]

Acquired Immunodeficiency Syndrome (Aids) was initially related to HIV-associated wasting syndrome, and its metabolic disturbances to altered body composition. After Highly Active Antiretroviral Therapy (HAART) was started, malnutrition has declined and HIV-associated lipodystrophy syndrome has emerged as an important metabolic disorder. Aids is also characterized by hormonal disturbances, principally in growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. The use of recombinant human GH (hrGH) was formerly indicated to treat wasting syndrome, in order to increase lean body mass. Even though the use of hrGH in lipodystrophy syndrome has been considered, the decrease in insulin sensitivity is a limitation for its use, which has not been officially approved yet. Diversity in therapeutic regimen is another limitation to its use in Aids patients. The present study has reviewed the main HIV-related endocrine-metabolic disorders as well as the use of hrGH in such conditions.

Absence of mutations in Pax6 gene in three cases of Morning Glory syndrome associated with isolated growth hormone deficiency

Morning glory syndrome (MGS) is a congenital optic disc dysplasia often associated with craniofacial anomalies, especially basal encephalocele and hypopituitarism. Clinical signs are varied and often occult. The PAX6 gene is involved in ocular morphogenesis and is expressed in numerous ocular tissues during development especially in the developing central nervous system. The aim of the present study is to evaluate PAX6 in MGS associated with isolated growth hormone deficiency. Three pre-pubertal males (A, B and C) with MGS and short stature due to growth hormone deficiency, treated with recombinant human growth hormone with limited response, were reported. Two of them had basal encephalocele. Coding and non-coding sequences corresponding of PAX6 different transcripts were analyzed by direct sequencing. Nucleotide variations causing putative aminoacid change were not observed. Patient A presented the new IVS2+9G>A transition, whereas patients A and C were heterozygous for known single nucleotide polymorphisms (SNP) within the intron 4. In addition, two SNP heterozygoses were observed for patient C in both intron 9 and 13. Sequencing also revealed several nucleotide variations in patient B. Two heterozygoses for known polymorphisms were identified along with a novel C>A nucleotide change in intron 4. This patient also presented a low number on the TG repeat in intron 9 and a new IVS11+33A>T transversion. Gene regulation and transcription of PAX6 are complex processes; there are two major protein isoforms, PAX6(-5a) and PAX6(+5a), and nine transcripts described. Furthermore, extra transcription regulatory elements have been postulated within PAX6 introns. Considering that neither population distributions on PAX6 polymorphism nor their linkeages with diseases have been reported, a functional effect due to alterations described here cannot be discarded.

Prevalence of allergic diseases and/or allergic sensitisation in children and adolescents with type 1 diabetes mellitus

BACKGROUND The prevalence of atopic diseases in children with type 1 diabetes mellitus (DM1) has been reported as lower. The aim of this study was to evaluate the prevalence of allergic diseases and allergic sensitisation in Brazilian children and adolescents with DM1. PATIENTS AND METHODS 96 patients with DM1 (aged 4-18 years, 45 boys) followed for at least one year were evaluated for allergic disease through a detailed allergological anamnesis and skin prick tests (SPT) to inhalant allergens (Dermatophagoides pteronyssinus, D. farinae, Blomia tropicalis, Blattella germanica, Periplaneta americana, dog epithelium, cat epithelium, mix fungi), foods (cows milk, egg-white, yolk, soy, wheat, corn), and positive (histamine 1 mg/ml) and negative (saline) controls. Wheals with a mean diameter of induration equal to or greater than 3mm identified a positive SPT. RESULTS The prevalence values of rhinitis, asthma and atopic eczema (isolated or associated) were 68.0%, 59.1% and 44.4%, respectively. 20.6% of the patients had no allergic disease. 46.8% of the patients had been diagnosed with DM1 for at least four years and there was no relationship between the period of DM1 and the presence of allergic disease, nor of the gender. 48.0% patients were sensitised with predominance of D. pteronyssinus, B. topicalis and D. farinae. The frequency of positive SPT was significantly higher among patients with history of allergic disease (OR=6.98, 95%CI: 2.60-18.74, p<0.001). CONCLUSION The prevalence of allergic diseases and sensitisation in patients with DM1 was higher than usually expected and deserves further investigation to identify possible causes for these findings and to evaluate their importance and influence on the metabolic control.

Early traits of metabolic syndrome in pediatric post-cancer survivors: outcomes in adolescents and young adults treated for childhood medulloblastoma

OBJECTIVE To analyze traits of metabolic syndrome (MetS) in medulloblastoma survivors. SUBJECTS AND METHODS Sixteen childhood medulloblastoma survivors aged 18.0 (4.4) years, with history of craniospinal radiation therapy (RT) were compared with nine control subjects matched by age, gender, and body mass index, according to fat distribution, metabolic and cardiovascular variables. RESULTS Medulloblastoma patients showed increases in waist circumference and its relationships (all p < 0.05), and HOMA1-IR (p = 0.006), which were modified by growth hormone (GH) secretion status. However, these increases were within normal range. CONCLUSIONS Adolescent and young adult survivors of medulloblastoma showed centripetal fat deposition and decreased insulin sensitivity, associated with GH status. Pediatric brain tumor survivors following RT should be monitored for the diagnosis of MetS traits predisposing to cardiovascular disease.