Seronegative Myasthenia Gravis, as a Rare Autoimmune Condition in Turner Syndrome.

Girls with Turner syndrome (TS), especially with isochromosome 46,X,i(X)(q10), are prone to develop autoimmunity. Associations of several autoimmune conditions with TS have been frequently described in the past. However, the unique combination of TS and myasthenia gravis (MG) has been reported only once before in a girl with mosaic monosomy 45,X/46,XX. Here, we present the second case of a girl affected with seronegative MG but with mosaic isochromosome TS. This is a child with developmental delay presented with muscle weakness, frequent fall, and bilateral ptosis. Diagnosis of MG was made based on positive Tensilon and electromyography tests and excellent response to intravenous immunoglobulin. At the age of 11 years due to short stature and developmental delay, a karyotype was done and revealed the mosaic isochromosome 45,X/46,X,i(X)(q10). Overall, clinicians should be aware of the vulnerability of girls with TS to autoimmunity, especially if the isochromosome 46,X,i(X)(q10) karyotype is identified. Furthermore, if a child with TS develops muscle weakness, ptosis, or ophthalmoplegia, MG should also be included in the differential diagnosis, particularly if other concurrent autoimmune conditions are present.

Timing of the Diagnosis of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder.

BACKGROUND AND OBJECTIVE: Symptoms of inattention, hyperactivity, and impulsivity are core features of attention-deficit/hyperactivity disorder (ADHD). However, children with autism spectrum disorder (ASD) often present with similar symptoms and may receive a diagnosis of ADHD first. We investigated the relationship between the timing of ADHD diagnosis in children with ASD and the age at ASD diagnosis. METHODS: Data were drawn from the 2011-2012 National Survey of Children's Health, which asked parents to provide the age(s) at which their child received a diagnosis of ADHD and/or ASD. Using weighted prevalence estimates, we examined the association between a previous diagnosis of ADHD and the age at ASD diagnosis, while controlling for factors known to influence the timing of ASD diagnosis. RESULTS: Our study consisted of 1496 children with a current diagnosis of ASD as reported by parents of children ages 2 to 17 years. Approximately 20% of these children had initially been diagnosed with ADHD. Children diagnosed with ADHD before ASD were diagnosed with ASD ∼3 years (95% confidence interval 2.3-3.5) after children in whom ADHD was diagnosed at the same time or after ASD. The children with ADHD diagnosed first were nearly 30 times more likely to receive their ASD diagnosis after age 6 (95% confidence interval 11.2-77.8). The delay in ASD diagnosis was consistent across childhood and independent of ASD severity. CONCLUSION: To avoid potential delays in ASD diagnosis, clinicians should consider ASD in young children presenting with ADHD symptoms.

Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6-10 years of age.

BACKGROUND: There is concern over potential neurobehavioral effects of prenatal phthalate exposures, but available data are inconsistent. OBJECTIVES: We examined associations between prenatal urinary concentrations of phthalate metabolites and neurobehavioral scores among children. METHODS: We measured phthalate metabolite concentrations in urine samples from 153 pregnant participants in the Study for Future Families, a multicenter cohort study. Mothers completed the Child Behavior Checklist when the children were 6-10 years of age. We estimated overall and sex-specific associations between phthalate concentrations and behavior using adjusted multiple regression interaction models. RESULTS: In boys, concentrations of monoisobutyl phthalate were associated with higher scores for inattention (ß = 0.27; 95% CI: 0.04, 0.50), rule-breaking behavior (ß = 0.20; 95% CI: 0.01, 0.38), aggression (ß = 0.34; 95% CI: 0.09, 0.59), and conduct problems (ß = 0.39; 95% CI: 0.20, 0.58), whereas the molar sum of di(2-ethylhexyl) phthalate metabolites was associated with higher scores for somatic problems (ß = 0.15; 95% CI: 0.03, 0.28). Higher monobenzyl phthalate concentrations were associated with higher scores for oppositional behavior (ß = 0.16; 95% CI: 0.01, 0.32) and conduct problems (ß = 0.21; 95% CI: 0.06, 0.37) in boys, but with reduced anxiety scores in girls (ß = -0.20; 95% CI: -0.39, -0.01). In general, the associations reported above were close to the null among girls. Model coefficients represent the difference in the square root-transformed outcome score associated with a 1-unit increase in log-transformed metabolites. CONCLUSIONS: Our results suggest associations between exposure to certain phthalates in late pregnancy and behavioral problems in boys. Given the few studies on this topic and methodological and population differences among studies, additional research is warranted.

Developmental neurotoxicity of ortho-phthalate diesters: review of human and experimental evidence.

Ortho-phthalate diesters, or phthalates, are widely used synthetic chemicals found primarily in consumer products and polyvinyl chloride plastics. Experimental evidence suggests that several phthalates possess antiandrogenic properties and may disrupt endocrine pathways resulting in abnormal reproductive outcomes. Low-level exposure to phthalates has been well documented in humans, with higher levels found in children and women of childbearing age. Recent epidemiologic studies postulate that prenatal exposure to measurable urine phthalate concentrations may be associated with altered genital and pubertal development in infants and children. This review addresses the emerging evidence that some phthalates may have an adverse impact on the developing brain. The supporting animal studies and proposed mechanisms underlying the deleterious properties of phthalates in relation to neurodevelopmental outcomes are also discussed. While the observed associations are based on limited studies with a broad range of endpoints, the implications of such outcomes are of concern from a public health standpoint and merit further investigation given the widespread nature of the exposure.

Polymorphisms in the maternal sex steroid pathway are associated with behavior problems in male offspring.

OBJECTIVE: Slight perturbations in maternal sex steroid production and metabolism may interfere with normal fetal neurodevelopment. The balance of maternal estrogens and androgens may have direct fetal effects, may influence the fetal hypothalamic-pituitary-gonadal axis, or may alter local hormonal activity within the fetal brain. We investigated maternal functional polymorphisms of CYP17, CYP19, and CYP1B1, which control three major enzymatic steps in sex steroid biosynthesis and metabolism, in relation to childhood behaviors. METHODS: The Mount Sinai Children's Environmental Health Study enrolled a multiethnic urban pregnancy cohort from 1998 to 2002 (n=404). DNA was obtained from maternal blood (n=149) and from neonatal cord blood (n=53). At each visit, mothers completed the Behavior Assessment System for Children, a parent-reported questionnaire used to evaluate children for behavior problems. We focused on problem behaviors more commonly associated with attention deficit-hyperactivity disorder (Hyperactivity, Attention Problems, Externalizing Behaviors, Conduct Disorder, Poor Adaptability) to determine whether maternal genetic variants in sex steroid production and metabolism influence sexually dimorphic behaviors in offspring. RESULTS: The more active gene variants were significantly associated with Attention Problems and poorer Adaptive Skills in male compared with female offspring. The CYP19 variant allele was also significantly associated with worse scores for boys on the Hyperactivity, Externalizing Problems Composite, and Adaptive Skills Composite scales (P<0.05). CONCLUSION: We observed maladaptive behaviors in the male offspring of mothers who carried functional polymorphisms in the sex steroid pathway. The strongest associations were in domains commonly affected in attention deficit-hyperactivity disorder.

Children's health and the environment: an overview.

Environmental pediatrics, the branch of pediatric medicine that studies the influence of the environment on children's health, has in the past decade grown exponentially. Rising rates of pediatric chronic disease and growing recognition of children's extensive exposures and great vulnerabilities to toxic hazards in the environment have catalyzed this expansion. New scientific initiatives have resulted. They include 14 Centers for Children's Environmental Health and Disease Prevention Research supported by the US National Institutes of Health and the US Environmental Protection Agency; a global network of Pediatric Environmental Health Specialty Units supported by the US Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry; new postdoctoral training programs in pediatric environmental medicine; and the National Children's Study, the largest prospective epidemiological study of children's health ever undertaken in the United States, which launched in 2009 and will follow 100,000 children from conception to age 21 to assess environmental influences on health and development. These research initiatives have delineated the exquisite vulnerability of fetuses, infants, and children to toxic hazards in the environment. They have led to discovery of new environmental causes of disease and disability in children. This issue of The Mount Sinai Journal of Medicine focuses on children's health and the environment. We have brought together thought leaders in children's environmental health to critically examine new research findings, to explore new opportunities for translating research to treatment and prevention, and to offer a vision for the future of this rapidly expanding field.

Environmental neurotoxicants and developing brain.

The brain of infants and children is uniquely sensitive to environmental neurotoxicants at levels far below those that are known to harm adults. There are multiple windows of vulnerability during which environmental exposures can interfere with normal development. The timing and duration of neurotoxicant exposures during development can give rise to a broad spectrum of structural and functional deficits. Only about 200 chemicals out of more than 80,000 registered with the United States Environmental Protection Agency have undergone extensive neurotoxicity testing, and many chemicals found in consumer goods are not required to undergo any neurodevelopmental testing. The cumulative effects of co-contaminants and the difficulties in analyzing biomarkers of exposure in human tissues have complicated comprehensive risk assessment. Furthermore, population-based studies that measure subtle effects on neurobehavioral outcomes are challenging to interpret and costly to conduct. Despite the fact that developmental neurotoxicity may be more severe and irreversible compared with adult toxicity, there is a relative paucity of toxicological data on developing systems for many high-production chemicals. This article provides an overview of the adverse neurological, cognitive, and behavioral outcomes associated with environmental exposures, with an emphasis on human studies.

Endocrine disruptors and childhood social impairment.

Prenatal exposure to endocrine disruptors has the potential to impact early brain development. Neurodevelopmental toxicity in utero may manifest as psychosocial deficits later in childhood. This study investigates prenatal exposure to two ubiquitous endocrine disruptors, the phthalate esters and bisphenol A (BPA), and social behavior in a sample of adolescent inner-city children. Third trimester urines of women enrolled in the Mount Sinai Children's Environmental Health Study between 1998 and 2002 (n=404) were analyzed for phthalate metabolites and BPA. Mother-child pairs were asked to return for a follow-up assessment when the child was between the ages of 7 and 9 years. At this visit, mothers completed the Social Responsiveness Scale (SRS) (n=137), a quantitative scale for measuring the severity of social impairment related to Autistic Spectrum Disorders (ASD) in the general population. In adjusted general linear models increasing log-transformed low molecular weight (LMW) phthalate metabolite concentrations were associated with greater social deficits (ß=1.53, 95% CI 0.25-2.8). Among the subscales, LMWP were also associated with poorer Social Cognition (ß=1.40, 95% CI 0.1-2.7); Social Communication (ß=1.86, 95% CI 0.5-3.2); and Social Awareness (ß=1.25, 95% CI 0.1-2.4), but not for Autistic Mannerisms or Social Motivation. No significant association with BPA was found (ß=1.18, 95% CI -0.75, 3.11). Prenatal phthalate exposure was associated with childhood social impairment in a multiethnic urban population. Even mild degrees of impaired social functioning in otherwise healthy individuals can have very important adverse effects over a child's lifetime. These results extend our previous finding of atypical neonatal and early childhood behaviors in relation to prenatal phthalate exposure.

Prenatal phthalate exposure is associated with childhood behavior and executive functioning.

BACKGROUND: Experimental and observational studies have reported biological consequences of phthalate exposure relevant to neurodevelopment. OBJECTIVE: Our goal was to examine the association of prenatal phthalate exposure with behavior and executive functioning at 4-9 years of age. METHODS: The Mount Sinai Children's Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urines were collected and analyzed for phthalate metabolites. Children (n = 188, n = 365 visits) were assessed for cognitive and behavioral development between the ages of 4 and 9 years. RESULTS: In multivariate adjusted models, increased loge concentrations of low molecular weight (LMW) phthalate metabolites were associated with poorer scores on the aggression [beta = 1.24; 95% confidence interval (CI), 0.15- 2.34], conduct problems (beta = 2.40; 95% CI, 1.34-3.46), attention problems (beta = 1.29; 95% CI, 0.16- 2.41), and depression (beta = 1.18; 95% CI, 0.11-2.24) clinical scales; and externalizing problems (beta = 1.75; 95% CI, 0.61-2.88) and behavioral symptom index (beta = 1.55; 95% CI, 0.39-2.71) composite scales. Increased loge concentrations of LMW phthalates were also associated with poorer scores on the global executive composite index (beta = 1.23; 95% CI, 0.09-2.36) and the emotional control scale (beta = 1.33; 95% CI, 0.18- 2.49). CONCLUSION: Behavioral domains adversely associated with prenatal exposure to LMW phthalates in our study are commonly found to be affected in children clinically diagnosed with conduct or attention deficit hyperactivity disorders.

The U.S. Food and Drug Administration risk assessment on lead in women's and children's vitamins is based on outdated assumptions.

BACKGROUND: Following a recent report of lead in certain commercial vitamin products, the U.S. Food and Drug Administration (FDA) conducted a nationwide survey to determine the Pb content in 324 multivitamin/mineral products labeled for use by women and children. The FDA compared estimated Pb exposures from each product with safe/tolerable exposure levels, termed provisional total tolerable intake (PTTI) levels, previously developed for at-risk population groups in 1992. OBJECTIVE: We investigated the FDA's conclusions that Pb concentrations in all vitamin products examined do not pose a hazard to health because they are below the PTTI levels for all groups considered. DISCUSSION: For their initial estimations of PTTI levels, the FDA used a blood lead level (BLL) of 10 microg/dL as the threshold for adverse effects in children and in pregnant or lactating women. Studies have repeatedly linked chronic exposure to BLLs < 10 microg/dL with impairments in cognitive function and behavior in young children despite the absence of overt signs of toxicity. The FDA analysis also omitted any consideration of nonfood sources of Pb exposure, which is inconsistent with our current understanding of how most children develop elevated BLLs. CONCLUSION: We feel that based on these oversights, the FDA's conclusions are unduly reassuring and that reconsideration of their current recommendations appears warranted.

Prenatal phthalate exposure and performance on the Neonatal Behavioral Assessment Scale in a multiethnic birth cohort.

We investigated the relationship between prenatal maternal urinary concentrations of phthalate metabolites and neonatal behavior in their 295 children enrolled in a multiethnic birth cohort between 1998 and 2002 at the Mount Sinai School of Medicine in New York City. Trained examiners administered the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) to children within 5 days of delivery. We measured metabolites of 7 phthalate esters in maternal urine that was collected between 25 and 40 weeks' gestation. All but two phthalate metabolites were over 95% detectable. We summed metabolites on a molar basis into low and high molecular weight phthalates. We hypothesized the existence of sex-specific effects from phthalate exposure a priori given the hormonal activity of these chemicals. Overall we found few associations between individual phthalate metabolites or their molar sums and most of the BNBAS domains. However, we observed significant sex-phthalate metabolite interactions (p<0.10) for the Orientation and Motor domains and the overall Quality of Alertness score. Among girls, there was a significant linear decline in adjusted mean Orientation score with increasing urinary concentrations of high molecular weight phthalate metabolites (B=-0.37, p=0.02). Likewise, there was a strong linear decline in their adjusted mean Quality of Alertness score (B=-0.48, p<0.01). In addition, boys and girls demonstrated opposite patterns of association between low and high molecular weight phthalate metabolite concentrations and motor performance, with some indication of improved motor performance with increasing concentration of low molecular weight phthalate metabolites among boys. This is the first study to report an association between prenatal phthalate exposure and neurological effects in humans or animals, and as such requires replication.