Patient Presentation
A 6-month-old male came to clinic with his mother. She said that he seemed to be developing normally, but was very concerned because her sister’s 3-year-old son had just been diagnosed with Fragile X syndrome during an evaluation for developmental delay. “They really don’t know much, just that they have a reason why he’s not normal. Looking back he’s always seemed a little different to me. He would look at me and other people a little differently and he just hasn’t been doing the things people would expect when he walks or talks. I’m really worried about my son. He’s not the same as my nephew but he’s also still little. Is there something we should do? Does he need to get tested for it,” she asked.

The pertinent physical exam showed an alert and interactive male with normal vital signs and growth parameters in the 75-95%. His physical examination was normal. Developmentally he had good eye contact, seemed to hear appropriately, would sit without support, would pull a toy to him, change hands and mouth the toy, and would says vowel sounds responsively.

The diagnosis of a healthy male was made. “At this time, he seems to be growing and developing appropriately and I’ll keep a close eye on him along with you. Fragile X can be passed from parents to their children. The best information is going to come from your sister. Once she knows more about her risks, then that will tell us more about your risks, and that of your son or other children you might have. At this time I don’t think we need to send him to a neurologist or developmental specialist but if he seems to be behind we can do that at any point. Also once we know more about your risks, I can have you talk with someone who will know more about it. Usually the people talking to your sister will also have recommendations for other family members like yourself. When you know more, let me know and we can decide together what to do,” the pediatrician said.

Discussion
Fragile X syndrome (FXS) was first clinically described in 1943 by Martin-Bell and in 1969 Lubs found a fragility at the terminal end of the X chromosome. In 1991, three different research groups independently cloned the mutation for the FMR1 gene (Fragile X mental retardation type 1) which has a CGG triplet expansion. The FMR1 gene codes for the FMR protein which is a major regulator of synaptic plasticity and is expressed in the brain and spermatogonia mainly but many other tissues during fetal and early neonatal development. The number of triplets and methylation correlates with clinical expression (increased numbers have increased clinical expression). It is an X-linked dominant gene with reduced penetrance. Overall it has an incidence of 1:4000 for males and 1:7000 in females.

Learning Point
FXS occurs from inactivation of the FMR1 gene. FXS is the most common cause of inherited intellectual disability. It is also a leading form of autism spectrum disorders. Patients may also have seizures, abnormal head movements, hyperactive behavior, and poor eye contact.

FXS is suspected in patients with developmental delays and is diagnosed by polymerase chain reaction which can determine the number of CGG repeats as well as other genetic information that is important for genetic counseling. The number of repeats tends to increase in subsequent generations especially with repeats in the permutation zone. People with 6-44 repeats are considered normal. People with 45-54 are in a gray zone where the alleles can be stable or unstable. From 55-200 repeats is the permutation zone. People with >200 repeats have the full mutation.

If the person is male, they have FXS. If they are female, 30-50% will be affected because of X-inactivation. FXS physical characteristics include “…elongated face, broad forehead, high palate, prominent ears, hyperextensible finger joints, flat feet and macroorchidism” but this is variable depending on age and ethnicity. Mitral valve prolapse, macrocephaly and scoliosis are also seen.

Clinical problems seen with the permutation includes women with impaired reproductive systems with decreased fertility and early menopause, psychiatric disorders (anxiety, depression and increased stress), pain syndromes, hypertension, sleep apnea, hypothyroidism, vertigo and olfaction and hearing problems. There also seems to be higher rates of attention deficit hyperactivity disorder, social problems and/or autism spectrum disorder. Fragile X tremor/ataxis syndrome also is an identified clinical problem for certain individuals. All of these problems vary greatly depending on the individual.

Gene therapy treatments are being evaluated, and medications targeting signal modulations are also being studied. Most treatment is a combination of behavioral, educational and medication to support and treat co-occurring problems.

Questions for Further Discussion
1. What is included in the differential diagnosis of intellectual disability?
2. What can pediatricians do for families affected by rare diseases? A review can be found here
3. Who can also provide genetic counseling if a genetic counselor is not available?
4. What should be included in the differential diagnosis of intellectual disability?

Related Cases

Disease: Fragile X Syndrome | Birth Defects

Symptom/Presentation: Health Maintenance and Disease Prevention

Specialty: Genetics | Medical History | Neurology / Neurosurgery | Developmental Disabilities

Age: Infant

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Fragile X Syndrome and Birth Defects.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Mila M, Alvarez-Mora MI, Madrigal I, Rodriguez-Revenga L. Fragile X syndrome: An overview and update of the FMR1 gene. Clin Genet. 2018;93(2):197-205. doi:10.1111/cge.13075

Salcedo-Arellano MJ, Dufour B, McLennan Y, Martinez-Cerdeno V, Hagerman R. Fragile X syndrome and associated disorders: Clinical aspects and pathology. Neurobiol Dis. 2020;136:104740. doi:10.1016/j.nbd.2020.104740

Glasson EJ, Buckley N, Chen W, et al. Systematic Review and Meta-Analysis: Mental Health in Children With Neurogenetic Disorders Associated With Intellectual Disability. J Am Acad Child Adolesc Psychiatry. January 2020. doi:10.1016/j.jaac.2020.01.006

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa