FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants.

PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.

Safety concerns regarding binge drinking in pregnancy: a review.

BACKGROUND: There is ongoing debate about the risks to the fetus associated with maternal binge drinking. This makes it difficult to counsel patients about the potential risks associated with their use of alcohol during pregnancy. METHODS: This article reviews the literature on animal and human studies regarding binge drinking (four to five drinks at one time in humans, or the equivalent in laboratory animals). RESULTS: Animal studies provide evidence that high doses of alcohol over a short period of time can be more damaging than lower doses over a long period of time. Human data are more inconsistent, especially in terms of the association with malformations. Although neurobehavioral effects are the most commonly reported adverse outcome, some studies do not find such an association. Conclusions are confounded by the design of many studies, which fail to document pattern and total amount of alcohol consumption at one time. In addition, it has been suggested there is a bias against the null effect in publications. CONCLUSION: Although the evidence in humans is not conclusive, the incidence of binge exposures in pregnancy is high, and it appears prudent to counsel patients to avoid this exposure whenever possible. Women inadvertently exposed to a single binge episode of alcohol early in the first trimester before pregnancy recognition can be reassured that the risks for adverse effects in their baby are likely low if they are able to discontinue use for the duration of the pregnancy. Unfortunately, there may be some residual fetal risk.

The art and science of teratogen risk communication.

Despite scientific advances in clinical teratology, exposures during pregnancy still cause great anxiety and misunderstanding. Patients and health care providers are frequently called upon to determine the health implications of scientific studies, which may involve limited and contradictory data. These findings are often conveyed numerically, which is a particularly difficult form of information for both patients and their health providers to understand and interpret. Almost half of the general population (and a substantial minority of physicians) have difficulty with numeracy. Patients with low numeracy tend to interpret information in an absolute manner and ignore uncertainty, have more difficulty using numeric information to inform their choices, and are more easily influenced by emotion and the format used in presenting information. Formats involved in conveying probability include positive or negative framing, use of relative versus absolute risk, and ratios and percentages. Health providers should communicate risk analysis in a fashion that facilitates comprehension and results in informed behavior. This is more likely to be achieved when risks are conceptualized as more than just numbers, and are considered in the context of individuals' life circumstances and values. Most teratogen risk communication is done over the telephone; this presents both advantages and challenges. Strategies are suggested to improve risk communication. These include avoiding the use of relative risk, using a consistent denominator, framing the information in a variety of ways (positive vs. negative), using verbal qualifiers judiciously, and employing visual aids.

Update on the developmental consequences of cannabis use during pregnancy and lactation.

There is a strong increase in prevalence trends for cannabis use during pregnancy and lactation as more states legalize use of this drug. Information on the teratogenic risk of cannabis is limited but some important themes can be gleaned. Studies have not found a unique phenotypic signature of prenatal exposure but an increased risk of congenital anomalies, particularly gastroschisis, has been reported. Changes in fetal growth have been described in some epidemiological studies but long-term patterns of physical growth appear unaffected. Prenatal exposure to cannabis is not generally associated with reductions in global IQ but specific cognitive skills, especially attention and memory, can be negatively impacted. Long-term impacts on psychological health include increased rates of depressive symptoms and anxiety as well as delinquency. Relatively little is known about the risk of maternal cannabis use during lactation but data suggest that infant exposure is relatively low compared to maternal exposure. As delta-9-tetrahydrocannabinol (THC) levels increase to meet consumer demand and routes of exposure diversify, there is a strong need for prospective birth-cohort studies that collect biological samples to quantify exposure. Data from such studies will be critical to overcoming the weaknesses of past cannabis research and are essential to establishing reliable information on the risks of maternal use. Until that time, health care providers should be encouraged to talk about the risks and benefits associated with cannabis use during pregnancy and lactation with their patients, emphasizing that fetal and neonatal risks cannot be excluded at this time.

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

OBJECTIVE: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. METHODS: We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. RESULTS: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. INTERPRETATION: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.

Herbal agents and over-the-counter medications in pregnancy.

Exposures to over-the-counter and herbal products are frequent in pregnant women. Limited information exists on the effects of many of these agents during pregnancy; it is not safe to assume that because these products are available without a prescription that they are without danger to the pregnant woman and her fetus. The basic principles utilized in deciding whether to employ prescription medications such as dose, embryological timing and potential toxic fetal effects also apply to herbal medications and over-the-counter agents. Conventional reasoning indicates that maternal exposure to poorly studied medications should be limited; therefore, many of these agents should be used sparingly or not at all by pregnant women. This chapter includes a review of selected herbal and over-the-counter agents, including those which are considered to be acceptable for use in pregnancy.

Use of herbal agents by breastfeeding women may affect infants.

Breastfeeding women increasingly are taking herbal medications. Physicians dealing with women wishing to breastfeed should ask specifically about use of herbal and non-traditional medications. Important questions include why the herbals are being used, what benefits the patient is attempting to achieve, and whether it is truly critical to take the herbal agent during the time of breastfeeding. There are often other medications with known safety profiles during breastfeeding that can be used instead. If the herbal medication is not critical to a woman's health, it can often be deferred during the time of breastfeeding, the safest way to avoid any potential complications. To be able to discuss these issues with mothers who are planning to breastfeed, the clinician must become aware of which herbal medications are in use and understand their potential side effects. The more knowledge the health professional has regarding complementary medicine, the more trust the patient will have in discussing these issues and working with the physician to minimize any dangers to the breastfeeding infant.