Nancy Roizen

Down's syndrome

The sequencing of chromosome 21 and the use of models of Downs syndrome in mice have allowed us to relate genes and sets of genes to the neuropathogenesis of this syndrome, and to better understand its phenotype. Research in prenatal screening and diagnosis aims to find methods to identify fetuses with Downs syndrome, and reduce or eliminate the need for amniocentesis. Other areas of active research and clinical interest include the association of Downs syndrome with coeliac disease and Alzheimers disease, and improved median age of death. Medical management of the syndrome requires an organised approach of assessment, monitoring, prevention, and vigilance. Improvements in quality of life of individuals with Downs syndrome have resulted from improvements in medical care, identification and treatment of psychiatric disorders (such as depression, disruptive behaviour disorders, and autism), and early educational interventions with support in typical educational settings. Approaches and outcomes differ throughout the world.

Outcome of Treatment for Congenital Toxoplasmosis, 1981–2004: The National Collaborative Chicago-Based, Congenital Toxoplasmosis Study

Background Without treatment, congenital toxoplasmosis has recurrent, recrudescent, adverse outcomes. Long-term follow-up of infants with congenital toxoplasmosis treated throughout their first year of life with pyrimethamine and sulfadiazine has not been reported. Methods Between 1981 and 2004, one hundred twenty infants (current mean age +/- standard deviation, 10.5 +/- 4.8 years) with congenital toxoplasmosis were treated with 1 of 2 doses of pyrimethamine plus sulfadiazine; therapy was initiated shortly after birth and continued for 12 months. Children who received treatment were evaluated at birth and at predetermined intervals; the focus of the evaluations was on prespecified end points: motor abnormalities, cognitive outcome, vision impairment, formation of new eye lesions, and hearing loss. Results Treatment of infants without substantial neurologic disease at birth with pyrimethamine and sulfadiazine for 1 year resulted in normal cognitive, neurologic, and auditory outcomes for all patients. Treatment of infants who had moderate or severe neurologic disease (as defined in this article in the Treatments subsection of Methods) at birth resulted in normal neurologic and/or cognitive outcomes for >72% of the patients, and none had sensorineural hearing loss. Ninety-one percent of children without substantial neurologic disease and 64% of those with moderate or severe neurologic disease at birth did not develop new eye lesions. Almost all of these outcomes are markedly better than outcomes reported for children who were untreated or treated for 1 month in earlier decades (P .05). Conclusions Although not all children did well with treatment, the favorable outcomes we noted indicate the importance of diagnosis and treatment of infants with congenital toxoplasmosis.

Velo-cardio-facial syndrome

Purpose of review Velo-cardio-facial syndrome has emerged from obscurity to become one of the most researched disorders this past decade. It is one of the most common genetic syndromes in humans, the most common contiguous gene syndrome in humans, the most common syndrome of cleft palate, and the most common syndrome of conotruncal heart malformations. Velo-cardio-facial syndrome has an expansive phenotype, a factor reflected in the wide range of studies that cover both clinical features and molecular genetics. In this review, we cover multiple areas of research during the past year, including psychiatric disorders, neuroimaging, and the delineation of clinical features. Recent findings The identification of candidate genes for heart anomalies, mental illness, and other clinical phenotypes has been reported in the past year with a focus on TBX1 for cardiac and craniofacial phenotypes and COMT and PRODH for psychiatric disorders. The expansive phenotype of velo-cardio-facial syndrome continues to grow with new behavioral and structural anomalies reported. Treatment issues are beginning to draw attention, although most authors continue to focus on diagnostic issues. Summary Its high population prevalence, estimated to be as common as 1:2000 has sparked a large amount of research, as has the model the syndrome serves for identifying the causes of mental illness and learning disabilities, but it is obvious that more information is needed. Intensive scrutiny of velo-cardio-facial syndrome will undoubtedly continue for many years to come with the hope that researchers will turn more of their attention to treatment and treatment outcomes.

Energy expenditure in children with Down syndrome: Correcting metabolic rate for movement

Children with Down syndrome (DS) have a high prevalence of obesity. To investigate the relation between energy expenditure and obesity, we measured body composition, resting metabolic rate (RMR), and total energy expenditure in 13 prepubescent children with DS and in 10 control subjects matched for age, weight, and percentage of fat, using indirect calorimetry and the doubly labeled water method. Measurement of RMR was complicated by excessive movement by both the DS and control subjects. We therefore developed a method of subtracting the energy expended in movement and calculated the corrected RMR. The corrected RMR was significantly lower in those with DS than in control subjects when expressed as a percentage of the basal metabolic rate, predicted by the World Health Organization: 79.5% +/- 10.4% and 96.8% +/- 7.8%, respectively (p < 0.001). No significant differences were detected in total daily energy expenditure or non-RMR expenditure between the subject groups. In the DS group, 60% of the variability in fat mass could be accounted for by non-RMR expenditure expressed per kilogram of body weight (p < 0.02). No relation was detected between fat mass and non-RMR expenditure in control subjects, nor were any measures of energy expenditure predictive of changes in fatness among the subjects with DS during a 1-year follow-up. The results of this study indicate that prepubescent children with DS have decreased RMR compared with control children.

Nutrient Intake and Obesity in Prepubescent Children with Down Syndrome

OBJECTIVE The aim of this study was to measure nutrient intake and body composition in prepubescent children with Down syndrome to understand dietary barriers involved in the prevention and treatment of obesity. DESIGN Dietary intake was determined from parent-reported 3-day diet records for children with Down syndrome and control subjects. Energy intake was compared with energy expenditure measured by the doubly labeled water method. Body composition was determined by deuterium dilution, bioelectrical impedance analysis, and skinfold thickness measurements. SUBJECTS/SETTING Ten prepubescent children with Down syndrome and 10 control subjects were recruited from the hospital community. The study was conducted in the Clinical Research Center of the University of Chicago Medical Center. MAIN OUTCOME MEASURES Nutrient intakes were compared with the Recommended Dietary Allowances (RDAs) to estimate risk for nutrient deficiency. Fat-free mass values determined by bioelectrical impedance analysis and measurement of skinfold thicknesses were compared with values determined using the deuterium dilution method. STATISTICAL ANALYSES PERFORMED Unpaired t tests were used for comparisons between subjects groups and the Wilcoxon signed-rank test was used for comparison of nutrient intakes with RDAs. RESULTS The subjects with Down syndrome were significantly shorter (P < .01) than control subjects; however, body composition did not differ between the groups. Reported energy intake was lower in subjects with Down syndrome. In addition, several micronutrients were consumed, especially among nonobese subjects with Down syndrome, at less than 80% of the RDA. APPLICATIONS To avoid lowering already inadequate intakes of several vitamins and minerals, we suggest that treatment of obesity in children with Down syndrome combine a balanced diet without energy restriction, vitamin and mineral supplementation, and increased physical activity.

Longitudinal Study of New Eye Lesions in Children with Toxoplasmosis Who Were Not Treated During the First Year of Life

PURPOSE To determine the incidence of new chorioretinal lesions in children with toxoplasmosis diagnosed after, and therefore not treated during, their first year. DESIGN Prospective longitudinal cohort study. METHODS Thirty-eight children were evaluated in Chicago between 1981 and 2005 for new chorioretinal lesions. Thirty-eight children and mothers had serum IgG antibody to Toxoplasma gondii. RESULTS Twenty-eight of 38 children had one of the following: diagnosis with serum antibody to T. gondii indicative of chronic infection at age 24 months, central nervous system calcifications, hydrocephalus, illness compatible with congenital toxoplasmosis perinatally but not diagnosed at that time. Twenty-five returned for follow-up during 1981 to 2005. Their mean (range) age at last exam was 10.9 +/- 5.7 (range, 3.5 to 27.2) years and mean follow-up was 5.7 +/- 2.9 years. Eighteen (72%) children developed at least one new lesion. Thirteen (52%) had new central lesions, 11 (44%) had new peripheral lesions, and six (24%) had both. Thirteen (52%) had new lesions diagnosed at age > or =10 years. New lesions were found at more than one visit in four (22%), and bilateral new lesions developed in seven (39%) of 18 children who developed new lesions. Of 10 additional children with eye findings and serologic tests indicative of chronic infection, six returned for follow-up, four (67%) developing new lesions at > or =10 years of age. CONCLUSIONS More than 70% developed new chorioretinal lesions. New lesions were commonly diagnosed after the first decade of life.

OPHTHALMIC DISORDERS IN CHILDREN WITH DOWN SYNDROME

The goal of this study was to determine the frequency of ophthalmic disorders in a group of young children with Down syndrome who were unselected for ophthalmic abnormalities, and to determine whether examination by a pediatric ophthalmologist should become standard practice. Of 77 children referred to a Down syndrome clinic at a teaching hospital and evaluated by a pediatric ophthalmologist, 61 per cent had ophthalmic disorders needing treatment and monitoring. Furthermore, the percentage of children with ophthalmic disorders increased with age, from 38 per cent in the two‐ to 12‐month‐old group to 80 per cent in the five‐ to 12‐year‐old group. The authors conclude that children with Down syndrome should be evaluated by a pediatric ophthalmologist in the first six months of life and annually thereafter.

Evidence for associations between the purinergic receptor P2X 7 (P2RX7) and toxoplasmosis

Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong proinflammatory responses. Ligation of ATP by purinergic receptor P2X7, encoded by P2RX7, stimulates proinflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X7 has a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z-scores ±2.429; P=0.015) between the derived C(+)G(−) allele (f=0.68; OR=2.06; 95% CI: 1.14–3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0–4.25; 0.004<P<0.009) when hydrocephalus was removed from the analysis. Association with toxoplasmic retinochoroiditis was replicated (FBAT Z-scores ±3.089; P=0.002) in a small family-based study (60 families; 68 affected offspring) of acquired infection in Brazil, where the ancestral T(+) allele (f=0.296) at SNP rs1718119 was strongly protective (OR=0.27; 95% CI: 0.09–0.80).

Depressive and obsessive-compulsive symptoms in hyperserotonemic parents of children with autistic disorder

Because of previous findings that parents of children with autistic disorder may be at increased risk for anxiety disorders and/or mood disorders, the Center for Epidemiological Studies-Depression (CES-D) Scale and the Modified Maudsley Obsessive-Compulsive Inventory (MMOCI) were administered to parents of children with autistic disorder and parents of children with Downs syndrome. Parents with normal whole blood serotonin levels who had children with autistic disorder and parents of children with Downs syndrome had significantly lower CES-D depression scores than parents with elevated whole blood serotonin levels who had children with autistic disorder. Hyperserotonemic parents of children with autistic disorder had significantly higher MMOCI scores than parents of children with Downs syndrome.

Promoting Optimal Development: Screening for Behavioral and Emotional Problems

By current estimates, at any given time, approximately 11% to 20% of children in the United States have a behavioral or emotional disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Between 37% and 39% of children will have a behavioral or emotional disorder diagnosed by 16 years of age, regardless of geographic location in the United States. Behavioral and emotional problems and concerns in children and adolescents are not being reliably identified or treated in the US health system. This clinical report focuses on the need to increase behavioral screening and offers potential changes in practice and the health system, as well as the research needed to accomplish this. This report also (1) reviews the prevalence of behavioral and emotional disorders, (2) describes factors affecting the emergence of behavioral and emotional problems, (3) articulates the current state of detection of these problems in pediatric primary care, (4) describes barriers to screening and means to overcome those barriers, and (5) discusses potential changes at a practice and systems level that are needed to facilitate successful behavioral and emotional screening. Highlighted and discussed are the many factors at the level of the pediatric practice, health system, and society contributing to these behavioral and emotional problems.