Fetal alcohol syndrome (FAS) is an irreversible congenital condition caused by maternal alcohol consumption during pregnancy. Its main symptoms are the triad of characteristic facial features, growth retardation, and central nervous system disorders.
FAS is the most severe form of fetal alcohol spectrum disorders (FASD). FASD includes alcohol-related neurodevelopmental disorder (ARND), alcohol-related birth defects (ARBD), and neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE).
The global prevalence of FASD is estimated at 7.7 per 1,000 people. The prevalence of FASD among schoolchildren in the United States is 0.6–5.0%. The lifetime cost per individual with FAS is approximately $2 million (estimated in 2002), resulting in an annual societal burden of over $4 billion in the United States.
Clinical diagnosis is made when two or more of the following four criteria are met.
For early diagnosis from the neonatal period, the RDSS (Revised Dysmorphology Scoring System) can be used, and a score of 5 or more out of 41 suggests FASD 1).
The global prevalence of FASD is estimated at 7.7 per 1,000 people. Among school-age children in the United States, FASD is found in 0.6–5.0%, making it far from a rare disorder.
Ophthalmic subjective symptoms in FAS mainly include decreased visual acuity and behavioral problems.
In FAS, findings are observed in a wide range of areas including the periorbital region, intraocular structures, and eye movements. Ophthalmic examination is useful for early diagnosis of FAS.
Periorbital findings
Short palpebral fissures (blepharophimosis): Horizontal palpebral fissures are shortened, which is the most important ophthalmic diagnostic criterion for FAS.
Epicanthal folds (Mongolian folds): Present in up to 80% of alcohol-exposed infants.
Microphthalmia: Associated with underdevelopment of the entire eyeball.
Telecanthus: Increased distance between the inner canthi.
Ptosis: Drooping of the upper eyelid, which may restrict the visual field.
Intraocular Findings
Optic nerve hypoplasia/optic atrophy: Observed in up to 48% of children with FAS in Sweden.
Retinal vascular tortuosity: Occurs in up to 49% of cases, a frequent finding in FAS.
Anterior segment abnormalities: Axenfeld-Rieger-like findings, Peters anomaly, glaucoma, and uveal coloboma have been reported.
Cataract: Rarely associated.
The following ocular motor and functional abnormalities are observed:
Alcohol is a known central nervous system teratogen that freely crosses the placenta. The following mechanisms are involved in the development of FAS:
The amount and pattern of alcohol consumption are important determinants of teratogenic effects. Binge drinking (heavy episodic drinking) has a particularly large impact on the fetus. The threshold for safe alcohol consumption remains unknown.
Mothers who are carriers of the fragile X syndrome (FXS) premutation (PM) have been reported to have a higher risk of alcohol and substance abuse 2). In cases of dual diagnosis of FXS and FAS, cognitive and behavioral impairments are additively more severe 2).
The threshold for safe alcohol consumption is unknown. Not only the amount of alcohol but also the pattern of drinking (binge drinking) significantly affects teratogenicity. Complete abstinence from alcohol is recommended during pregnancy.
The diagnosis of FAS is made clinically. Specific biomarkers have not been established.
Clinical diagnosis is made when two or more of four criteria (characteristic facial features, growth retardation, brain effects, and neurobehavioral effects) are met. Confirmed maternal alcohol exposure strengthens the diagnosis, but such information may not always be available.
Ophthalmic examination is useful for early diagnosis of FAS, and the following is recommended.
The main evaluation items and scoring of the RDSS score are shown below.
| Evaluation item | Finding | Score (example) |
|---|---|---|
| Vermilion border | Thin | 2–4 points |
| Nasolabial fold | Smooth | 2–4 points |
| Head circumference | Microcephaly | 2–4 points |
The RDSS has a maximum of 41 points, with a score of 5 or higher suggesting FASD 1). In one case report, a 3-day-old male infant with thin vermilion border, smooth philtrum, microcephaly, flat nasal bridge, and long philtrum was scored 15 points 1).
The following diseases are similar to FAS:
FAS is an irreversible condition with no curative treatment. Abstinence from alcohol during pregnancy is the only preventive measure. Treatment aims to reduce secondary disabilities and improve quality of life.
Early detection combined with behavioral therapy and special education is the most important factor in improving outcomes. Individualized treatment through multidisciplinary collaboration is recommended.
There is no specific medication for FAS. If attention-deficit/hyperactivity disorder (ADHD) is comorbid, stimulants may be used.
FAS can be complicated by cardiac malformations such as atrial septal defect (ASD). Mild cases are managed with observation, but severe cases require surgical repair. In one reported case, ASD was not diagnosed until the patient was 34 years old, leading to secondary pulmonary hypertension4).
FAS is an irreversible disease and cannot be cured. However, early intervention (behavioral therapy, special education, ophthalmologic management) can reduce secondary disabilities and improve quality of life. For details, refer to the “Standard Treatment” section.
The teratogenic effects of alcohol are exerted through multiple pathways.
Neural Crest Cell Toxicity
Direct cell death: Alcohol induces apoptosis in anterior neural crest cells that organize the forebrain.
Facial and brain structural abnormalities: Reduction of neural crest cells leads to characteristic facial features and brain structural anomalies.
Epigenetic abnormalities
DNA methylation abnormalities: Cause permanent changes in gene expression patterns.
Histone modification abnormalities: Chromatin structure changes, disrupting neuroplasticity.
Retinoic acid inhibition
Competitive inhibition of synthetic enzymes: Alcohol and retinoic acid share common metabolic enzymes.
Facial dysmorphism: Reduced retinoic acid signaling causes midface developmental disorders.
In animal models, optic nerve hypoplasia is observed as a reduction in retinal ganglion cells and axon density, damage to glial cells, and impairment of myelin sheaths.
As for effects on brain structure, disproportionate volume reduction in the basal ganglia, cerebellum, and corpus callosum has been reported 2). These structural brain changes underlie saccadic abnormalities and attention deficits.
Koren et al. (2021) administered CBD (cannabidiol) to 5 patients with FASD and reported a significant improvement in Nisonger Disruptive Behavior scores from 18±1.0 to 6±2.1 (p=0.0002)3). Example doses included 2 drops/day of CBD oil (20%) for a 5-year-old and 3 drops/morning of CBD oil (15% CBD + 1% THC) for a 12-year-old. Marked improvements in aggression, impulsivity, and restlessness were observed, with no reported side effects.
However, this study was an open-label study with only 5 cases, and the types and routes of administration of cannabinoids used were not standardized3). Future large-scale randomized controlled trials are needed.
The possibility of preventing FASD through choline supplementation during embryogenesis or administration of natural antioxidants is being investigated. Antioxidants found in cruciferous vegetables may reduce alcohol-induced stress on neural crest cells.
