Correlation between morphological MRI findings and specific diagnostic categories in fetal alcohol spectrum disorders

Fetal alcohol spectrum disorders (FASD) include physical and neurodevelopmental abnormalities related to prenatal alcohol exposure. Some neuroimaging findings have been clearly related to FASD, including corpus callosum and cerebellar anomalies. However, detailed studies correlating with specific FASD categories, that is, the fetal alcohol syndrome (FAS), partial FAS (pFAS) and alcohol related neurodevelopmental disorders (ARND), are lacking. We prospectively performed clinical assessment and brain MR imaging to 72 patients with suspected FASD, and diagnosis was confirmed in 62. The most frequent findings were hypoplasia of the corpus callosum and/or of the cerebellar vermis. Additional findings were vascular anomalies, gliosis, prominent perivascular spaces, occipito-cervical junction and cervical vertebral anomalies, pituitary hypoplasia, arachnoid cysts, and cavum septum pellucidum.     

Fetal alcohol spectrum disorders: Extending the range of structural defects

Although the structural phenotype of fetal alcohol syndrome (FAS) is established, prenatal exposure to alcohol may produce a broader spectrum of defects, fetal alcohol spectrum disorder (FASD). Documenting the full spectrum of defects associated with FASD is critical to determining the true incidence of this disorder. We examined 831 children from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders using a structured protocol for diagnosis of FAS using the cardinal facial and growth features, and assessment of additional structural defects thought to occur more often in children with prenatal alcohol exposure. Subjects were classified as FAS, Deferred (some characteristic features of FAS), or No FAS, Groups were compared on prevalence of additional features and number of additional features observed, stratified by diagnostic category, sex, race, and age. Prevalence of most additional features was greatest among subjects with FAS and least among No FAS. A higher frequency of additional features was observed among FAS and Deferred subjects ≥12 years of age than among those under 12. FAS and Deferred Whites had greater frequency of additional features than Cape Colored. Prenatal alcohol exposure may produce a broad spectrum of structural defects that goes beyond FAS with implications regarding the impact of alcohol on the developing fetus, a prerequisite for ultimate prevention of FASD.     

Relationship between dysmorphic features and general cognitive function in children with fetal alcohol spectrum disorders

Prenatal alcohol exposure may adversely affect fetal development, causing growth restriction, distinctive craniofacial anomalies, and central nervous system dysfunction. The continuum of associated adverse fetal outcomes is most accurately termed fetal alcohol spectrum disorders (FASD). The purpose of this study was to further clarify the relationship between dysmorphic features and general cognitive capacity in a study on Finnish children with FASD. Forty-eight 8- to 16-year-old children with FASD underwent a dysmorphology examination and an assessment of cognitive capacity. Dysmorphic features and growth deficiency were quantified by assigning each child a total dysmorphology score (TDS). Six subtests from the Wechsler Intelligence Scale for Children (WISC-III) were used for assessment of general cognitive capacity. Our results show a significant correlation between the TDS and cognitive capacity was found, suggesting that children with more severe growth deficiency and dysmorphic features have more cognitive limitations. Birth measures of length and weight correlated with general cognitive capacity. Head circumference correlated only with Performance IQ. These findings imply an inverse relationship between growth deficiency/dysmorphic features and cognitive function in children with FASD. Although the correlations are significant, the data suggest that in individual cases, the TDS cannot reliably predict cognitive function in later life.     

A review of the physical features of the fetal alcohol spectrum disorders

The fetal alcohol spectrum of disorders (FASD) includes four diagnostic categories for the clinical consequences of prenatal alcohol exposure (PAE) in the unborn child. Physical features are necessary for the diagnosis of the fetal alcohol syndrome (FAS) and partial pFAS. Moreover, these features are specific and a diagnosis of FAS can be made even in the absence of knowledge of PAE. Not only growth deficits, microcephaly and the 3 facial features (short palpebral fissures, smooth philtrum and narrow vermillion of the upper lip) are characteristic, since other dysmorphic features particularly in the hands are key to the recognition of FAS. Most features can be explained by the damage to the brain during pregnancy and can be replicated in animal models. Many different diagnostic guidelines are used for the diagnosis of FASD and the physical features are considered differently in each of them. There is a need for universal clinical criteria for the diagnosis of FASD if our goal is to favor universal recognition.     

Diagnostic outcomes of 27 children referred by pediatricians to a genetics clinic in the Netherlands with suspicion of fetal alcohol spectrum disorders

The characteristics of fetal acohol spectrum disorders (FASD) constitute a specific facial phenotype, growth failure and neurodevelopmental defects. Reported FASD prevalences vary widely from 0.08 per 1,000 up to 68.0–89.2 per 1,000. We aimed to evaluate to which extent children referred with a suspicion of FASD, indeed have FASD. We included all 27 children referred to our genetic department with a suspicion of FASD between 2005 and 2010. Nineteen children (70.3%) were of non‐Dutch ancestry, and 24 (88.9%) had been adopted. We used both the 4‐Digit Code and the Revised Institute of Medicine criteria. More than half of the children did not meet either criteria for the diagnosis of FASD. Of note, after evaluation 8/27 children appeared not to have confirmed prenatal alcohol exposure. Two children referred for suspicion of FASD (neither of which were exposed to alcohol or met the criteria for FASD) had a pathogenic microstructural chromosomal rearrangement (del16p11.2 of 542 KB and dup1q44 of 915 KB). In 22/24 children (91.7%) there were other factors that may have affected their intellectual abilities, such as familial intellectual disability and social deprivation. We recommend a critical approach towards the diagnosis FASD, and to investigate all patients suspected to have FASD for other causative factors including genetic abnormalities. © 2013 Wiley Periodicals, Inc.     

Challenges of diagnosis in fetal alcohol syndrome and fetal alcohol spectrum disorder in the adult

Adults with fetal alcohol syndrome (FAS) and the subsets of individuals with attenuated phenotype subsumed under the umbrella term of fetal alcohol spectrum disorder (FASD) provide clinicians with a challenge. Compounding this, FASD is different from most genetic syndromes since a specific diagnostic biological test is not available. The diagnosis first needs to be suspected and confirmation requires a diagnostic assessment that is best carried out in the context of a multi-disciplinary team approach. There is surprisingly little research published on the prevalence, natural history, medical, and social complications relevant to adults with FASD. The evidence that is emerging suggests that this disorder is common, and that services to diagnose and treat these individuals are limited. Adults with FASD have a higher incidence of impairments in social adaptive and executive function, and a higher degree of psychopathology when compared to the general population. The impact of FASD has significant and serious effects on those affected with FASD, their families, and our communities. There is a need for improved access to diagnosis, and more research and evaluation of interventions currently in use. In this paper, we describe the current diagnostic criteria, the differential diagnosis, the prevalence, natural history, the behavioral and mental health consequences, medical and social management issues, and interventions for adults affected with this disorder.     

Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling

Consumption of alcohol by pregnant women can cause fetal alcohol spectrum defects (FASD), a congenital disease, which is characterized by an array of developmental defects that include neurological, craniofacial, cardiac, and limb malformations, as well as generalized growth retardation. FASD remains a significant clinical challenge and an important social problem. Although there has been great progress in delineating the mechanisms contributing to alcohol-induced birth defects, gaps in our knowledge still remain; for instance, why does alcohol preferentially induce a spectrum of defects in specific organs and why is the spectrum of defects reproducible and predictable. In this study, we show that exposure of zebrafish embryos to low levels of alcohol during gastrulation blocks covalent modification of Sonic hedgehog by cholesterol. This leads to impaired Hh signal transduction and results in a dose-dependent spectrum of permanent developmental defects that closely resemble FASD. Furthermore, supplementing alcohol-exposed embryos with cholesterol rescues the loss of Shh signal transduction, and prevents embryos from developing FASD-like morphologic defects. Overall, we have shown that a simple post-translational modification defect in a key morphogen may contribute to an environmentally induced complex congenital syndrome. This insight into FASD pathogenesis may suggest novel strategies for preventing these common congenital defects.     

Ocular measurements in fetal alcohol spectrum disorders

Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and neurologic deficits in individuals exposed to alcohol prenatally. Reduced palpebral fissure length is one of the cardinal facial features of FASD. However, other ocular measurements have not been studied extensively in FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how inner canthal distance (ICD), interpupillary distance (IPD), and outer canthal distance (OCD) centiles differed between FASD and non‐FASD individuals. We compared ocular measurement centiles in children with FASD to non‐FASD individuals and observed reductions in all three centiles for ICD, IPD, and OCD. However, when our non‐FASD children who had various forms of growth deficiency (microcephaly, short‐stature, or underweight) were compared to controls, we did not observe a similar reduction in ocular measurements. This suggests that reductions in ocular measurements are a direct effect of alcohol on ocular development independent of its effect on growth parameters, which is consistent with animal models showing a negative effect of alcohol on developing neural crest cells. Interpupillary distance centile appeared to be the most significantly reduced ocular measure we evaluated, suggesting it may be a useful measure to be considered in the diagnosis of FASD.     

Two brothers with macrocephaly, progressive cerebral atrophy and abnormal white matter, severe mental retardation, and Lennox-Gastaut spectrum type epilepsy: an inherited encephalopathy of childhood?

Two brothers with severe mental retardation of unknown origin were found to share several physical anomalies, including large round head, small concave nose, downslanted palpebral fissures, and gingival hyperplasia. In addition to relative macrocephaly, magnetic resonance imaging (MRI) showed severe cerebral atrophy, especially fronto-temporally. The brothers also had a thin corpus callosum and atrophic caudate nuclei. The reduced white matter showed patchy periventricular signal intensity changes. The lateral and third ventricles were large, but the fourth ventricle was of normal size. The boys had large cisterna magna, communicating widely with the fourth ventricle, but no vermian hypoplasia. Both boys had Lennox-Gastaut spectrum type epilepsy. No chromosomal anomalies were found, despite the suggestive clinical picture. Some of the clinical findings resembled fetal alcohol effects/fetal alcohol syndrome (FAE/FAS), which was also suggested by history. Current diagnostic criteria for FAE/FAS, however, excluded full-blown FAS in these cases and failed to explain the entire clinical picture in the boys. We argue that these boys had an unidentified inherited syndrome, possibly modified by fetal alcohol exposure.     

Minor Physical Anomalies and Learning Disability: What is the Prenatal Component?

The authors performed a case-control study of 60 school children who were examined for a constellation of anomalies suggestive of fetal alcohol exposure. Nonretarded learning disabled children were 7.25 times (95%, confidence interval, 1.05 to 50.0) more likely than controls to have signs consistent with alcohol exposure in fetal life. These data suggest an expanded spectrum of fetal alcohol effects. Early recognition of minor physical anomalies could result in prompt evaluation and treatment of these children.     

Prevalence of alcohol consumption during pregnancy and Fetal Alcohol Spectrum Disorders among the general and Aboriginal populations in Canada and the United States

Prenatal alcohol exposure may cause a number of health complications for the mother and developing fetus, including Fetal Alcohol Spectrum Disorders (FASD). This study aimed to estimate the pooled prevalence of i) alcohol use (any amount) and binge drinking (4 or more standard drinks on a single occasion) during pregnancy, and ii) Fetal Alcohol Syndrome (FAS) and FASD among the general and Aboriginal populations in Canada and the United States, based on the available literature. Comprehensive systematic literature searches and meta-analyses, assuming a random-effects model, were conducted. It was revealed that about 10% and 15% of pregnant women in the general population consume alcohol in Canada and the United States, respectively, and that about 3% of women engage in binge drinking during pregnancy in both countries. However, the prevalence of alcohol use during pregnancy in the Aboriginal populations of the United States and Canada were found to be approximately 3–4 times higher, respectively, compared to the general population. Even more alarmingly, it was estimated that approximately one in five women in the Aboriginal populations in both countries engage in binge drinking during pregnancy. Further, among the general population of Canada, the pooled prevalence was estimated to be about 1 per 1000 for FAS and 5 per 1000 for FASD. However, compared to the general population, the prevalence of FAS and FASD among the Aboriginal population in Canada was estimated to be 38 times and 16 times higher, respectively. With respect to the United States, the pooled prevalence of FAS and FASD was estimated to be about 2 per 1000 and 15 per 1,000, respectively, among the general population, and 4 per 1000 and 10 per 1,000, respectively, among the Aboriginal population. The FAS and FASD pooled prevalence estimates presented here should be used with caution due to the limited number of existing studies and their methodological limitations. Based on the results of the current study, it is evident that there is an urgent need for implementing more effective national prevention and surveillance strategies to monitor and lower the prevalence of alcohol consumption during pregnancy and FASD.     

Prenatal alcohol exposure causes attention deficits in male rats

Children with fetal alcohol spectrum disorder (FASD) are often diagnosed with attention-deficit/ hyperactivity disorder (ADHD). These children show increases in reaction time (RT) variability and false alarms on choice reaction time (CRT) tasks. In this study, adult rats prenatally exposed to ethanol were trained to perform a CRT task. An analysis of the distribution of RTs obtained from the CRT task found that rats with a history of prenatal ethanol exposure had more variable RT distributions, possibly because of lapses of attention. In addition, it was found that, similar to children with FASD, the ethanol-exposed rats had more false alarms. Thus, rats with prenatal ethanol exposure show attention deficits that are similar to those of children with FASD and ADHD.     

Comparing Attentional Networks in fetal alcohol spectrum disorder and the inattentive and combined subtypes of attention deficit hyperactivity disorder

The Attention Network Test (ANT) was used to examine alerting, orienting, and executive control in fetal alcohol spectrum disorder (FASD) versus attention deficit hyperactivity disorder (ADHD). Participants were 113 children aged 7 to 10 years (31 ADHD-Combined, 16 ADHD-Primarily Inattentive, 28 FASD, 38 controls). Incongruent flanker trials triggered slower responses in both the ADHD-Combined and the FASD groups. Abnormal conflict scores in these same two groups provided additional evidence for the presence of executive function deficits. The ADHD-Primarily Inattentive group was indistinguishable from the controls on all three ANT indices, which highlights the possibility that this group constitutes a pathologically distinct entity.     

A controlled social skills training for children with fetal alcohol spectrum disorders

Children with fetal alcohol spectrum disorders (FASD) have significant social skills deficits. The efficacy of a child friendship training (CFT) versus a delayed treatment control (DTC) was assessed for 100 children ages 6 to 12 years with FASD. Children in the CFT showed clear evidence of improvement in their knowledge of appropriate social behavior, and according to parent report, CFT resulted in improved social skills and fewer problem behaviors compared with DTC. Gains were maintained at 3-month follow-up. After receiving treatment, the DTC group exhibited similar improvement. Teachers did not report improvement as a function of social skills treatment. The findings suggest that children with FASD benefit from CFT but that these social skills gains may not be observed in the classroom.     

Comparing Attentional Networks in Fetal Alcohol Spectrum Disorder and the Inattentive and Combined Subtypes of Attention Deficit Hyperactivity Disorder

The Attention Network Test (ANT) was used to examine alerting, orienting, and executive control in fetal alcohol spectrum disorder (FASD) versus attention deficit hyperactivity disorder (ADHD). Participants were 113 children aged 7 to 10 years (31 ADHD–Combined, 16 ADHD–Primarily Inattentive, 28 FASD, 38 controls). Incongruent flanker trials triggered slower responses in both the ADHD–Combined and the FASD groups. Abnormal conflict scores in these same two groups provided additional evidence for the presence of executive function deficits. The ADHD–Primarily Inattentive group was indistinguishable from the controls on all three ANT indices, which highlights the possibility that this group constitutes a pathologically distinct entity.     

胎儿酒精谱系障碍的筛查工具与诊断标准

胎儿酒精谱系障碍是指母孕期酒精暴露导致的从胎儿轻度损伤到典型的胎儿酒精综合征的一系列障碍谱系，被公认为导致胎儿缺陷与儿童发育迟滞的主要原因之一，其症状包含四大类特征：胎儿宫内发育迟滞和／或出生后发育迟滞：中枢神经系统功能异常；颜面特征畸形（眼睑裂短、人中平以及上唇薄等）；母孕期酒精暴露。本文介绍该胎儿酒精谱系障碍的筛查工具和诊断标准。     

Phosphodiesterase type 1 inhibition improves learning in rats exposed to alcohol during the third trimester equivalent of human gestation

Deficits in learning and memory have been extensively observed in animal models of fetal alcohol spectrum disorders (FASD). Here we use the Morris maze to test whether vinpocetine, a phosphodiesterase type 1 inhibitor, restores learning performance in rats exposed to alcohol during the third trimester equivalent of human gestation. Long Evans rats received ethanol (5 g/kg i.p.) or saline on alternate days from postnatal day (P) 4 to P10. Two weeks later (P25), the latency to find a hidden platform was evaluated (2 trials per day spaced at 40-min inter-trial intervals) during 4 consecutive days. Vinpocetine treatment started on the first day of behavioral testing: animals received vinpocetine (20 mg/kg i.p.) or vehicle solution every other day until the end of behavioral procedures. Early alcohol exposure significantly affected the performance to find the hidden platform. The average latency of ethanol-exposed animals was significantly higher than that observed for the control group. Treatment of alcohol-exposed animals with vinpocetine restored their performance to control levels. Our results show that inhibition of PDE1 improves learning and memory deficits in rats early exposed to alcohol and provide evidence for the potential therapeutic use of vinpocetine in FASD.     

Inhibition of cerebellar granule cell turning by alcohol

Ectopic neurons are often found in the brains of fetal alcohol spectrum disorders (FASD) and fetal alcohol syndrome (FAS) patients, suggesting that alcohol exposure impairs neuronal cell migration. Although it has been reported that alcohol decreases the speed of neuronal cell migration, little is known about whether alcohol also affects the turning of neurons. Here we show that ethanol exposure inhibits the turning of cerebellar granule cells in vivo and in vitro. First, in vivo studies using P10 mice demonstrated that a single intraperitoneal injection of ethanol not only reduces the number of turning granule cells but also alters the mode of turning at the EGL–ML border of the cerebellum. Second, in vitro analysis using microexplant cultures of P0–P3 mouse cerebella revealed that ethanol directly reduces the frequency of spontaneous granule cell turning in a dose-dependent manner. Third, the action of ethanol on the frequency of granule cell turning was significantly ameliorated by stimulating Ca²⁺ and cGMP signaling or by inhibiting cAMP signaling. Taken together, these results indicate that ethanol affects the frequency and mode of cerebellar granule cell turning through alteration of the Ca²⁺ and cyclic nucleotide signaling pathways, suggesting that the abnormal allocation of neurons found in the brains of FASD and FSA patients results, at least in part, from impaired turning of immature neurons by alcohol.     

Importance of accurate diagnosis in counseling for neural tube defects diagnosed prenatally

In cases of fetal neural tube defects (NTD), termination of pregnancy without ascertainment of specific etiology may lead to provision of incorrect recurrence risks and erroneous diagnosis in future pregnancies. Four patients are presented who illustrate the etiologic diversity of neural tube defects. The patients were referred for prenatal diagnosis because of elevated maternal serum alphafetoprotein (AFP). All four chose pregnancy termination. Diagnostic methods included fetal ultrasound, amniocentesis for fetal karyotyping and amniotic fluid AFP/acetylcholinesterase (AChE) and/or fetal karyotyping after delivery, and dysmorphology evaluation of the fetus after intact delivery. These cases highlight the benefits of fetal karyotype analysis and of an intact delivery and thorough clinical examination of the fetus when patients choose to terminate pregnancies with fetal anomalies.     

Prenatal alcohol exposure and ability, academic achievement, and school functioning in adolescence: a longitudinal follow-up

BACKGROUND: Prenatal alcohol exposure is associated with learning, behavioral, and academic problems even in children without the fetal alcohol syndrome (FAS). OBJECTIVE: To examine the prenatal alcohol exposure and ability, academic achievement, and school functioning in adolescence. METHODS: In a longitudinal cohort, intelligence, academic performance, and school functioning were evaluated in 265 low socioeconomic status (SES) adolescents (M age = 15.1 years), 128 prenatally exposed to alcohol, 53 controls, and 84 special education students by using the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III) and the Wechsler Individual Achievement Test (WIAT). School records were abstracted for grade point averages (GPA), standardized achievement test scores, conduct, attendance, and special education placement. RESULTS: Alcohol-affected youth had significantly lower IQs than those in the other three groups. CONCLUSION: Although academic achievement (WIAT scores) was most impaired in the special education group who showed lower performance over all as well as in reading and spelling, alcohol-affected youth showed significant deficits on mathematics subtests. There was no increased incidence of conduct problems in school records related to alcohol exposure.