An assessment of obesity and hyperphagia in individuals with Smith-Magenis syndrome

Smith-Magenis syndrome (SMS;OMIM# 182290) is a multiple congenital anomalies and mental retardation syndrome caused by a 3.7- Mb deletion on chromosome 17p11.2 or a mutation in the RAI1 gene. Although the majority of the SMS phenotype has been well described, limited studies are available describing growth patterns in SMS. There is some evidence that individuals with SMS develop obesity. Thus, this study aims to characterize the growth and potential influence of hyperphagia in a cohort of individuals with SMS. A retrospective chart review was conducted of 78 individuals with SMS through Baylor College of Medicine (BCM) at Texas Children¡¯s Hospital (TCH.) All documented height and weight measurements were abstracted and Z-scores (SD units) for height-for-age, length-for-age and BMI-for-age were calculated. Mail-out questionnaires were provided to the corresponding parents of the cohort to assess for the presence of hyperphagia through a validated hyperphagia questionnaire (HQ). Analysis of this data demonstrates that by the age ¡Ý 20 years males with SMS have mean BMI¡¯s in the 85th-90th percentile corresponding to an overweight BMI, and females with SMS had mean BMI¡¯s in the 95th -97th percentile corresponding to an obese BMI. Parents indicated that hyperphagia is present in individuals with SMS as 76% of parent¡¯s report having to lock food away from their child. Females¡¯ age ¡Ý 20 years of age had the highest mean behavior, drive and severity scores as well as the highest BMI. Thus, this study concludes that it appears overweight and obesity, as well as hyperphagia, are present in this cohort of SMS individuals. The results of this study will hopefully enable parents and caregivers of children with SMS to take preventative measures in order to control food related behaviors present in their children as well as to prevent overweight and obesity and the associated negative health consequences.

Role of germ line p53 mutations in aneuploidy and immortalization of dermal fibroblasts from Li-Fraumeni cancer patients

Pedigree analysis of certain families with a high incidence of tumors suggests a genetic predisposition to cancer. Li and Fraumeni described a familial cancer syndrome that is characterized by multiple primary tumors, early age of onset, and marked variation in tumor type. Williams and Strong (1) demonstrated that at least 7% of childhood soft tissue sarcoma patients had family histories that is readily explained by a highly penetrant autosomal dominant gene. To characterize the mechanism for genetic predisposition to many tumor types in these families, we have studied genetic alterations in fibroblasts, a target tissue from patients with the Li-Fraumeni Syndrome (LFS).^ We have observed spontaneous changes in initially normal dermal fibroblasts from LFS patients as they are cultured in vitro. The cells acquire an altered morphology, chromosomal anomalies, and anchorage-independent growth. This aberrant behavior of fibroblasts from LFS patients had never been observed in fibroblasts from normal donors. In addition to these phenotypic alterations, patient fibroblasts spontaneously immortalize by 50 population doublings (pd) in culture; unlike controls that remain normal and senesce by 30-35 (2). At 50 pd, immortal fibroblasts from two patients were found to be susceptible to tumorigenic transformation by an activated T24 H-ras oncogene (3). Approximately 80% of the oncogene expressing transfectants were capable of forming tumors in nude mice within 2-3 weeks. p53 has been previously associated with immortalization of cells in culture and cooperation with ras in transfection assays. Therefore, patients' fibroblast and lymphocyte derived DNA was tested for point mutations in p53. It was shown that LFS patients inherited certain point mutations in one of the two p53 alleles (4). Further studies on the above LFS immortal fibroblasts have demonstrated loss of the remaining p53 allele concomitant with escape from senescence. While the loss of the second allele correlates with immortalization it is not sufficient to transformation by an activated H-ras or N-ras oncogene. These immortal fibroblasts are resistant to tumorigenic transformation by v-abl, v-src, c-neu or v-mos oncogene; implying that additional steps are required in the tumorigenic progression of LFS patients' fibroblasts.^ References. (1) Williams et al., J. Natl. Cancer Inst. 79:1213, 1987. (2) Bischoff et al., Cancer Res. 50:7979, 1990. (3) Bischoff et al., Oncogene 6:183, 1991. (4) Malkin et al., Science 250:1233, 1990. ^

Long range physical map of the Wilms' tumor - aniridia region on human chromosome 11

Nephroblastoma or Wilms' tumor is a pediatric renal malignancy that is the most frequently occurring childhood solid tumor. Approximately 1-2% of children with Wilms' tumor also present with aniridia, a congenital absence of all or part of the iris of the eye. These children also have high rates of genitourinary anomalies and mental retardation resulting in what is called the WAGR (Wilms' tumor, aniridia, genitourinary anomaly, mental retardation) syndrome. Cytogenetic analysis of metaphase chromosomes from these patients revealed a consistent deletion of band P13 on chromosome 11. These observations suggest close physical linkage between the disease-related loci, and further imply that development of each phenotype results from the loss of normal gene function.^ The objective of this work is to understand the molecular events at chromosome band 11p13 that are essential to the development of sporadic Wilms' tumor and sporadic aniridia. Two human/hamster somatic cell hybrids have been used to identify sixteen independent DNA probes that map to this segment of the human genome. These newly identified DNA probes and four previously reported probes (CAT, FSHB, D11S16, and HBVIS) have been used to subdivide 11p13 into five intervals defined by overlapping constitutional deletions from several WAGR patients. A long-range physical map of 11p13 has been constructed using each of these probes in Southern blot analysis of genomic DNA after digestion with infrequently cutting restriction enzymes and pulse-field gel electrophoresis. This map, established primarily with MluI and NotI, spans approximately 13 $\times$ 10$\sp{6}$ bp and encompasses deletion and translocation breakpoints associated with genitourinary anomalies, aniridia, and sporadic Wilms' tumor. This complete physical map of human chromosome band 11p13 enables us to localize the genes for sporadic Wilms' tumor and sporadic aniridia to a small number of specific NotI fragments. ^

Community diagnosis: A working tool for developing culturally appropriate diarrhea intervention programs

Most studies related to diarrhea have been focused narrowly on the etiological and pathophysiological factors involved in inducing the disease. Such studies have often failed to consider other facets contributing to and possibly prolonging the problem, namely: socio-economic conditions, educational opportunities and attainments, cultural characteristics and beliefs, and the political administration and its commitment towards fulfilling its moral and ethical obligations in responding to and fostering human development.^ This study utilized the diagnostic approach of the PRECEDE model. The acronym stands for the predisposing reinforcing, and enabling constructs in educational diagnosis and evaluation. The constituents of this model were identified by utilizing participant observation field methods, traditionally applied by ethnographers to collect data describing the multiple facets of a culture, and linguistic anthropology used to capture and define characteristic semantics and viewpoints. The household study sample was randomly selected from a defined list of households known to have at least one child less than five years of age. An open-ended questionnaire format was used to interview the 115 mothers in the selected households sample.^ Kalama, the study community, is characteristically an agricultural village, situated in the Governorate of Kaliobia and located approximately 25 Km (about 15.5 miles) from the capital, Cairo, Egypt. The 1986 census indicates a population size of 13,328 people in 4,818 households. There were 65 deaths occurring among children less than five years in 1986. The causes of death were primarily related to diarrhea, followed by upper respiratory infections, congenital anomalies and birth injuries.^ This study outlines (a) practices related to the management of diarrhea, including the administration of foods and drinks during such episodes; (b) influences of governmental policies; and (c) recommended strategies for overcoming barriers and promoting effective diarrhea intervention programs. ^

First -year mortality and survival among infants with selected congenital anomalies in Texas, 1995 to 1997

Congenital anomalies have been a leading cause of infant mortality for the past twenty years in the United States. Few registry-based studies have investigated the mortality experience of infants with congenital anomalies. Therefore, a registry-based mortality study was conducted of 2776 infants from the Texas Birth Defects Registry who were born January 1, 1995 to December 31, 1997, with selected congenital anomalies. Infants were matched to linked birth-infant death files from the Texas Department of Health, Bureau of Vital Statistics. One year Kaplan-Meier survival curves, and mortality estimates were generated for each of the 23 anomalies by maternal race/ethnicity, infant sex, birth weight, gestational age, number of life-threatening anomalies, prenatal diagnosis, hospital of birth and other variables. ^ There were 523 deaths within the first year of life (mortality rate = 191.0 per 1,000 infants). Infants with gastroschisis, trisomy 21, and cleft lip ± palate had the highest first year survival (92.91%, 92.32%, and 87.59%, respectively). Anomalies with the lowest survival were anencephaly (5.13%), trisomy 13 (7.41%), and trisomy 18 (10.29%). ^ Infants born to White, Non-Hispanic women had the highest first year survival (83.57%; 95% CI: 80.91, 85.88), followed by African-Americans (82.43%; 95% CI: 76.98, 86.70) and Hispanics (79.28%; 95% CI: 77.19, 81.21). Infants with birth weights ≥2500 grams and gestational ages ≥37 weeks also had the highest first year survival. First year mortality drastically increased as the number of life-threatening anomalies increased. Mortality was also higher for infants with anomalies that were prenatally diagnosed. Slight differences existed in survival based on infant's place of delivery. ^ In logistic regression analysis, birth weight (<1500 grams: OR = 7.48; 95% CI: 5.42, 10.33; 1500–2499 grams: OR = 3.48; 95% CI: 2.74, 4.42), prenatal diagnosis (OR = 1.92; 95% CI: 1.43, 2.58) and number of life-threatening anomalies (≥3: OR = 22.45; 95% CI: 11.67, 43.18) were the strongest predictors of death within the first year of life for all infants with selected congenital anomalies. To achieve further reduction in the infant mortality rate in the United States, additional research is needed to identify ways to reduce mortality among infants with congenital anomalies. ^