Fetal Alcohol Syndrome Mini Review
Abstract
Fetal Alcohol Syndrome (FAS) is characterized by central nervous system abnormalities, atypical facial features, and growth deficits. Its prevalence is estimated to be in the category of >1/1,000. It is caused by prenatal alcohol exposure and can be diagnosed via physical exam and neurological/cognitive assessment. Before diagnosis, it should be distinguished from facial dysmorphology of other genetic conditions, microcephaly, prenatal and postnatal growth deficits, and several mental health disorders. It is best managed by early individualized, targeted interventions, such as academic skills and caregiver training. Individuals with FAS have a shortened life expectancy. However, the best prognosis includes early diagnosis, targeted interventions, and a stable and nurturing living environment.
Keywords: prenatal alcohol exposure, facial dysmorphism, fetal alcohol spectrum disorders, central nervous system abnormalities
Introduction
Alcohol is a commonly consumed and widely available drug in the United States. Despite its prevalence, it can have a negative impact, especially on developing humans or fetuses. "Prenatal alcohol exposure (PAE) is a leading cause of preventable mental disability and birth defects in the Western world" (Kaminen-Ahola, 2020). The most severe disorder caused by prenatal alcohol exposure is Fetal Alcohol Syndrome (FAS). FAS is characterized by atypical facial features, growth defects, and central nervous system abnormalities. In addition, intellectual disability and symptoms of several major mental disorders are often present.
Early diagnosis and individualized treatment interventions can provide the best outcomes for individuals with FAS. This review will summarize the epidemiological, clinical, diagnostic, and pathological mechanisms of FAS. In addition, it will provide a discussion of differential diagnoses, management, and syndrome prognosis.
Review
Fetal Alcohol Syndrome (FAS) is one of four conditions in the overall category of Fetal Alcohol Spectrum Disorders. The Orpha number for this condition is 1915 (Orphanet: Fetal Alcohol Syndrome). Of the four spectrum disorders, FAS is the condition with the most significant number of symptom criteria. It is characterized by "at least 2 characteristic facial features, growth retardation, clear evidence of brain involvement, neurobehavioral impairment, with or without documented prenatal alcohol exposure" (Weitzman et al., 2022). This syndrome is "caused by excessive maternal consumption of alcohol during pregnancy" (Orphanet: Fetal Alcohol Syndrome). It is classified as a "congenital malformation of the nervous system" by a "category X drug (absolute contraindication in pregnancy)" (Dudek, 2014).
Information regarding the incidence of FAS varies. Based on a 2017 meta-analysis, the international prevalence of all Fetal Alcohol Spectrum Disorders is 0.77 percent (Weitzman et al., 2022). The prevalence of FAS in the United States is 0.2 percent in the general population (Weitzman et al., 2022). In addition, the Centers for Disease Control and Prevention stated that the incidence ranges from 0.2 - 1.5 in every 1000 live births and .03 out of 1,000 in children aged 7 to 9 (CDC, 2022). Given the statistical range, FAS most likely falls in the >1/1,000 category.
Characteristic facial features of FAS include "short palpebral fissures, thin vermillion border, and smooth philtrum" (Weitzman et al., 2022). First, individuals with FAS have a shortened area between the inner canthus and the outer canthus of the eye. This area is called the palpebral fissure. The second facial feature involves the border surrounding the red/pink part of the lips or the vermillion border. This border can be thinner in individuals with FAS. Finally, a smooth ridge between the upper lip and the nose or smooth philtrum can also be present in FAS. Two of these facial dysmorphisms or anatomical malformations must be present to meet the criteria for FAS (Weitzman et al., 2022). These facial dysmorphisms can be diagnosed during a physical examination.
In addition to facial dysmorphisms, FAS can be diagnosed when height or weight are "<10th percentile for age, sex, race/ethnicity at any point of time (prenatal or postnatal)" (Weitzman et al., 2022). Clinically, this deficiency is termed growth retardation. The growth of individuals with FAS will be slowed from fetal development to puberty. "Short stature may persist into adolescence and adulthood, although the pubertal growth spurt may temporarily mask short stature when the child approaches puberty" (Weitzman et al., 2022). In addition to facial abnormalities and growth deficits, individuals with FAS may have congenital heart disease and associated defects, skeletal anomalies, renal abnormalities, ocular anomalies, and auditory deficits (Weitzman et al., 2022). A physical examination can diagnose growth deficits, decreased head circumference, and the above congenital structural anomalies.
The third diagnostic criterion is "clear evidence of brain involvement, neurobehavioral impairment…" (Weitzman et al., 2022). Clear evidence can be demonstrated by the atypical structure of the central nervous system, neurologic abnormalities, and atypical functions of the central nervous system (Weitzman et al., 2022). For example, in addition to growth deficits, the circumference of the head may also be atypical. Specifically, "decreased head circumference (usually defined as ≤10th percentile for age and sex or if height and weight are <10th percentile, head circumference ≤3rd percentile) "(Weitzman et al., 2022). In addition, "corpus callosum, cerebellum, or basal ganglia" may have atypical size and shape (Weitzman et al., 2022). Neurological abnormalities could include seizures, "abnormal reflexes, abnormal tone, cranial nerve deficits" (Weitzman et al., 2022). These neurological abnormalities can also be diagnosed during a physical examination.
The atypical function of the central nervous system may not be observable until early childhood. Some features include cognitive impairment, executive functioning, memory, poor motor functions, difficulty sustaining attention, and social skill deficits. Social skills deficits and motor function can be assessed earlier. However, many of these other deficits may not be fully measurable in infants. For example, the brain's frontal lobe completes development later in life and has implications for executive functioning skills. Executive functioning skills include planning, organizing, and making judgments.
Regarding cognitive impairments, "children with FAS tend to have lower IQs than children with" the other forms of Fetal alcohol spectrum disorder (Weitzman et al., 2022). "Difficulties in arithmetic are the most common, but difficulties in reading and spelling also may occur; other cognitive problems may include impaired memory and slow processing speed" (Weitzman et al., 2022). Neurocognitive or psychoeducational assessments, such as intelligence and academic achievement assessments, can be used to determine cognitive impairments. However, this diagnostic method will likely require an interdisciplinary team, which can also assist with management and treatment.
In addition to the primary clinical criteria, individuals with FAS may have symptoms common in some mental health disorders. The symptoms include difficulty sustaining or maintaining attention, insomnia or problems with sleeping, atypical eating behaviors, and difficulty with impulse control and judgment (Weitzman et al., 2022). A behavioral assessment using validated behavioral screening tests is an excellent diagnostic method for these symptoms (Weitzman et al., 2022).
The diagnostic criteria include facial dysmorphisms, growth deficits, and central nervous system abnormalities. FAS can be diagnosed with or without prenatal alcohol exposure. This is important due to the potential negative impact, such as stigmatization, which can be associated with this syndrome. Prenatal alcohol exposure is measured by consuming six or more drinks per week for two or more weeks or three or more per occasion on two or more occasions (Weitzman et al., 2022). There is no quantity of alcohol consumption determined to be safe for normal prenatal development.
Other diseases or syndromes with overlapping symptoms and clinical manifestations should be considered during the diagnostic process. These include facial dysmorphology of other genetic conditions, microcephaly, and prenatal and postnatal growth deficits (Weitzman et al., 2022). In addition, a differential diagnosis for the following mental health disorders should also be completed; attention deficit hyperactivity disorder, autism spectrum disorder, intellectual disability, oppositional defiant disorder, conduct disorder, mood disorders, disinhibited social engagement disorder, reactive attachment disorder, posttraumatic stress disorder, sleep disorder, substance use disorder, and schizophrenia (Weitzman et al., 2022).
Early diagnosis of FAS before the age of six is one of several factors that can decrease the adverse outcomes of FAS (Weitzman et al., 2022). In addition, early diagnosis can lead to educational accommodations and support earlier in development. Educational and social services are another factor that leads to fewer adverse outcomes (Weitzman et al., 2022). Other factors include a "stable and nurturing living environment and absence of exposure to physical, sexual, or other types of violence" (Weitzman et al., 2022). Individuals with undiagnosed and untreated Fetal Alcohol spectrum disorders are forecasted to be "at high risk for adverse life outcomes from 'secondary disabilities.' These include inappropriate sexual behavior, disrupted school experience, trouble with the law and incarceration, homelessness, unemployment, substance use, chronic mental health problems, and premature death" (Weitzman et al., 2022).
It is best to provide individualized care for managing and treating FAS. Care tailored to the unique strengths and challenges of each family and individual with FAS will provide the most benefit. In addition, "early intervention may ameliorate some of the central nervous system effects of prenatal alcohol exposure (eg, on language and emotional dysregulation) and prevent associated problems (eg, academic, legal, psychiatric problems)" (Weitzman et al., 2022). The following targeted interventions have demonstrated short-term benefits; academic skills interventions and accommodations, specifically in mathematics, executive functioning interventions, social skills training, adaptive or life skills training, and caregiver training (Weitzman et al., 2022). In addition to these interventions and skills training, medication for attentional deficits, mood disorders," maladaptive behaviors including aggression," and anxiety can be prescribed. However, studies have "reported conflicting findings of the effectiveness of medication for the treatment of ADHD and other comorbid neuropsychiatric conditions and limited data for other symptom domains" (Weitzman et al., 2022).
FAS is caused by prenatal exposure to alcohol which impacts DNA and typical human growth processes. "The toxic effect of alcohol is partly caused by its oxidation product acetaldehyde, which is highly reactive toward DNA, consequently damaging chromosomes and mutating stem cells" (Kaminen-Ahola, 2020). In addition, alcohol reduces the activity of essential enzymes, specifically DNA methyltransferase 1, in the DNA methylation process (Kaminen-Ahola, 2020). Interestingly, one allele has demonstrated protection from facial dysmorphism in FAS. In a 2006 study, Das et al. concluded that the "ADH1B*3 allele is protective for the effects of maternal ethanol ingestion during pregnancy on offspring facial formation".
The most severe types of FAS are correlated with high maternal consumption of alcohol "during the initial weeks of pregnancy (6-9)" (Morena-Barrio et al., 2018). Although many pathological mechanisms have been proposed, the evidence has not supported any specific model. "Recently a new pathogenic model suggests that glycosylation defects underlie FAS based on the interference of alcoholism in the glycosylation, a major post-translational modification, and the overlapping clinical presentations of FAS and congenital disorders of glycosylation" (Morena-Barrio et al., 2018). Morena-Barrio et al.'s 2018 study examined if mechanisms of hypoglycosylation are also the root of FAS. This study was small, N= 25, but demonstrated "missense/splice site variants were more frequent in FAS than controls" (Morena Barrio et al., 2018). In addition, one patient with FAS and several siblings with FAS carried two variants that impacted his functioning (Morena-Barrio et al., 2018). Overall, this study provided evidence for more extensive studies on the impact of variants of N-glycosylation genes and prenatal alcohol exposure (Morena-Barrio et al., 2018).
Conclusion
FAS is the most severe of the Fetal Alcohol Spectrum Disorders. It is caused by prenatal exposure to alcohol. FAS is characterized by facial dysmorphism, growth deficits, and central nervous system abnormalities. Most of the diagnostic criteria above can be determined during a physical exam. However, an interdisciplinary team will be able to assess and support the central nervous system abnormalities and symptoms similar to many mental health disorders.
Although the exact pathological mechanisms have yet to be elucidated, a few probable mechanisms and genetic links can be further studied. Alcohol's oxidation product damages chromosomes and reduces the ability of the enzymes essential to the DNA methylation process (Kaminen-Ahola, 2020). Evidence suggests glycosylation defects could be the root of FAS, given the presence of variants compared to controls. Another genetic study has demonstrated protective effects from prenatal alcohol consumption on facial dysmorphism by the ADH1B*3 allele. Additional studies on the pathological and genetic mechanisms could help providers to improve treatment and screen for markers that lead to more severe cases of this spectrum of disorders.
Currently, FAS is best managed and treated with early intervention and individualized care. Targeted interventions such as academic skills interventions, social skills training, and caregiver training can also decrease the adverse outcomes of FAS. Although the syndrome presents features similar to many mental health disorders, medication treatment may not be as effective. Studies comparing medication's impact on neurotransmitters in FAS and similar mental health disorders could provide avenues to improve medical treatment.
List of Abbreviations Used
FAS or Fetal Alcohol Syndrome
PAE or Prenatal Alcohol Exposure
References
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