Marfan syndrome is a pleiotropic genetic connective tissue disorder most commonly involving the cardiovascular, skeletal, and ocular systems, which have abundant connective tissue. It is not known to affect the central nervous system, therefore developmental delays or cognitive involvement are not typically associated. We present a case of a 2-year-old Hispanic male who was diagnosed with autism spectrum disorder (ASD) because of poor social interaction, lack of eye contact, and speech delays. Several months after the ASD diagnosis and receiving therapies without improvement, he was unexpectedly found to have severe myopia and bilateral ectopia lentis. These findings prompted further evaluation that subsequently led to a clinical and molecular diagnosis of Marfan syndrome. After correction of his refractive error, his social skills and eye contact had significantly improved and his speech gradually caught up and resolved to a normal level for his age. This report emphasizes the need for comprehensive investigation of children with delays to include ocular assessments before determining ASD in the context of developmental delays.
A 2-year-old generally healthy male initially had presented with concerns for developmental delays and autistic behaviors at around 18 months of age. His parents noticed at this age that he was not communicating because he had no words and was not pointing to objects. An audiological evaluation, ordered by his pediatrician, was normal. Once enrolled in school at age 22 months, his prekindergarten teachers were particularly concerned that he preferred to play by himself rather than interacting with age-matched peers, had poor eye contact, and had difficulty focusing and engaging. Parents agreed to initiate speech therapy around age 22 months as recommended by the school psychologist. By 24 months of age, he still did not have any words, but occasionally babbled, and sporadically said “mama” and “papa.” Before formal autism evaluations, parents reported some repetitive play, including arrangement of cars and animal toys, which was not excessive. There were no other reported impairing restrictive behaviors or stereotypical motor movements.
The speech delay and the impaired social interaction prompted neurodevelopmental evaluations and the eventual diagnosis of autism spectrum disorder (ASD). The patient was seen by a developmental pediatrician and multiple psychologists, 1 of them who had specialized behavior training at an autism institute. The developmental pediatrician administered the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up that showed increased risk for ASD; therefore, he referred him for diagnostic evaluation. The behavioral psychologist, after assessing him thoroughly, concluded that he had a severe language delay, “most likely given the social isolation, plus an excessive use of electronic screens,” which was not the case per parents. He finally was diagnosed with ASD and categorized as severity level 1, “requiring support,” per the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Parents disagreed with this diagnosis and attributed his speech delays to poor social stimulation secondary to the coronavirus disease 2019 pandemic restrictions. Subsequent evaluations reported minimal improvement in his expressive language after several months of therapy and no improvement in his social skills. During this time, his teachers noticed he was only able to focus on objects that were in very close proximity to him and subsequently suggested that parents perform a vision exam because of concerns for poor vision.
Ophthalmologic evaluation revealed severe myopia and lens dislocation bilaterally. He was given eyeglasses to correct his refraction error and prevent amblyopia. Given this combination of ocular abnormalities, he was referred to genetics for evaluation of possible Marfan syndrome (MS). Before his genetics evaluation, a complete cardiology evaluation, including an echocardiogram, was recommended. Echocardiogram was notable for a dilated aortic root, with a z score of 2.2.
Upon assessment, the geneticist clinically diagnosed the patient with MS because of meeting the clinical criteria in the absence of known family history by presenting with ectopia lentis and an aortic diameter Z ≥2.1 His physical exam was notable for height above the 95th percentile and a normal MS systemic score (<7). Genetic testing later identified a de novo heterozygous pathogenic c.640G >A (p.Gly214Ser) variant in the FBN1 gene, confirming a molecular diagnosis of MS.
Shortly after his severe myopia was corrected, his parents and teachers reported a dramatic and significant improvement in his social interaction with his classmates and remarkable progress in his language development in the following weeks. On a reevaluation several months after the MS diagnosis, the patient had advanced in development appropriately. His vocabulary increased significantly to about 200 words. He was able to construct 3-word sentences and interact more appropriately with parents, teachers, and classmates. As such, reevaluation by neurodevelopmental specialists and speech therapy were discontinued. Parents consented to submission of this case report for publication.
Discussion
Our patient exhibited some of the prototypical manifestations of autism, such as limited eye contact, speech delay, and deficits in social communication and social interaction. Although his repetitive play was not excessive or impairing, it was still considered a contributing factor in his ASD diagnosis. He was subsequently diagnosed with ASD on the basis of these findings. However, thorough sensory testing was not completed, because an eye exam was not performed before his neuropsychological evaluations and final ASD diagnosis. The diagnosis of ASD generated anxiety and social stigma for the parents and relatives; as such, multiple assessments by different providers for second opinions and the utilization of speech therapy were requested by the parents.
Of note, the most recent ASD management guidelines published in 2020 from the American Association of Pediatrics mention that a vision exam should be performed in children with poor eye contact as part of a comprehensive evaluation.2
This case highlights how primary care pediatricians should be aware of the possibility of other diagnoses beyond ASD in the setting of developmental delays and poor social skills. In addition, it is important to note that repetitive behaviors are not unique to autism, and can be seen in children with normal development and those with other developmental disorders.3 Pediatricians should also keep in mind that multiple genetic and metabolic conditions are associated with autism, and some others can mimic it. Our case illustrates that further investigations of other organ systems are necessary to obtain a thorough clinical assessment of each patient, which could lead to other unexpected diagnoses, before labeling children with developmental delays with an ASD diagnosis. We recognize that MS and ASD can occur together, which was not the case in our patient. However, MS is not reported to affect the central nervous system (CNS) and cognition. Thus, if they occur in the same individual, these are most likely independent conditions.
We note that homocystinuria was also part of the differential before the results of the molecular testing returned. Homocystinuria is an autosomal recessive inborn error of methionine metabolism caused by the deficiency of the enzyme cystathionine β synthase. This disorder can manifest with Marfanoid habitus (including pectus deformities and tall stature), bilateral lens dislocation (typically downward), and CNS involvement manifested as developmental delays and intellectual disability. Despite being unable to obtain a plasma homocysteine sample from the patient, the results of the multigene testing panel, which included the cystathionine β synthase gene associated with classic homocystinuria, returned positive for FBN1 only and therefore obviated the need for this assay.
Other differential diagnoses to consider are Loeys-Dietz syndrome and Shprintzen-Goldberg syndrome. Loeys-Dietz syndrome is an autosomal dominant condition that has high phenotypic similarity to MS, such as aortic root dilation, but is not associated with ectopia lentis. Shprintzen-Goldberg syndrome is another autosomal dominant disorder associated with a similar marfanoid phenotype and highly penetrant CNS involvement with milder and less frequent cardiovascular manifestations.
Given that MS is an autosomal dominant genetic condition4 and that 75% of affected individuals have an affected parent, and that the mother was 12 weeks pregnant with their second child with the same father at the time of the evaluation, both parents had targeted FBN1 variant testing, despite being healthy with no medical concerns associated with MS. Parental variant testing returned negative, meaning that our patient’s heterozygous variant was likely de novo.
Patients with MS are recommended to establish care with cardiology, ophthalmology, and orthopedics for close surveillance of disease progression.
From the cardiac standpoint, our patient will need a repeat echocardiogram 6 months after the discovery of his aortic dilation to monitor progression and determine risk for aortic dissection. This will guide the cardiologist to decide when to start medications such as β blockers. Annual monitoring is recommended if his aortic dilation remains stable. The 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery guidelines recommend monitoring of the aortic root diameter.5
From the vision standpoint, early and aggressive correction of the refraction error is recommended to avoid amblyopia in children with MS. Our patient will need at least annual monitoring, because he is at greater risk of developing cataracts, glaucoma, and retinal detachment.6 Orthopedics referral is also indicated for initial evaluation and assessment for scoliosis, which can become an issue later in life.7
An important point to discuss is the restrictions of physical activity, especially at the age of our patient, in the setting of speech delays and history of social isolation during his early infancy. Restricting our patient from engaging in age-appropriate physical activity, such as running while playing with his peers, is in general not acceptable. This practice will only generate stigmatization and deprive him of social interactions and stimulation, which are necessary to maximize social and communication skills. Later on, this will become an important topic to discuss with parents and with the patient as he grows old and transitions to ownership of his care. Recent guidelines emphasize that physical activity is advised in patients with aortopathy, including aortic dilation.8 However, most of the data with respect to physical activity recommendations pertain to adults. Still, the general recommendation is to avoid competitive and contact sports, and promote recreational noncompetitive sports and exercise.
We acknowledge that our report is limited to only 1 case. However, the average patient with a rare condition visits 7.3 providers to receive an accurate diagnosis, similar to our patient.9 Our report serves as a reminder to consider contributing pathology in other organ systems, even for highly prevalent conditions such as developmental delays in which the clinical presentation appears to be straightforward.
Dr Mares Beltran and Ms Nesheiwat conceptualized and designed the article, drafted the initial manuscript, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURE: The authors have indicated they have no conflicts of interest relevant to this article to disclose.
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