Running head: FRAGILE X SYNDROME 1

Fragile X Syndrome Case Study

Genetic Counseling for Ms. Anderson

Patient’s mother, Ms. Anderson, reported for genetic counseling with the pediatric Nurse

Practioner. Ms. Anderson is a single mother of a 3-year-old child recently diagnosed with

Fragile X-associated mental retardation. Child presents with developmental delay and small

joint hyperextensibility. Ms. Anderson is pregnant with a second child at 14 weeks gestation.

Family history is unremarkable.

Fragile X syndrome (FXS) is a genetic mutation that presents on the X chromosome.

This mutation, found within the FMR1 gene at the fraXq27.3 site (Hammer & McPhee, 2019, pp.

18-19) is passed down through generations and the effects, mental retardation, small joint

hyperextensibility, macrocephaly, macroorchidism (large testes), long face, and protruding jaw,

and Autism-like behaviors, become more severe with each generation.

Fragile X Genetic Mutation

FXS is a genetic mutation on the X sex chromosome, and since both males and females

carry the X sex chromosome, the mutation can be passed to offspring by either parent. However,

when a male is a carrier, they produce females that are nonpenetrant, and the mutation is never

transmitted to male offspring (Hammer & McPhee, 2019, p. 17). On the other hand, when a

female is a carrier or is affected by FXS, she has a 50% chance of giving birth to an affected

child of either sex (Dean, Muthuswamy, & Agarwal, 2016).

FXS is located at Xq27.3 of the fragile X mental retardation 1(FMR1) gene and produces

the fragile X mental retardation protein (FMRP) (Dean et al., 2016). FMRP is responsible for the

translation of messenger ribonucleic acid (mRNA) and contains the base pairs of CGG (Hammer

& McPhee, 2019, p. 19). Normal base pairs of deoxyribonucleic acid (DNA) are adenine (A),

cytosine (C), guanine (G), and thymine (T), and the order of the base pairs determines what
FRAGILE X SYNDROME 3

information is carried on the individual genes. In FXS, there is a repeat of the sequence CGG,

which can vary in length and repeats (Hammer & McPhee, 2019, p. 19). Dean et al. (2019) state:

“the full mutation is positively associated with the length of the premutation in the transmitting

female”. Meaning, the greater the number of repeats in the CGG sequencing, the more likely the

FXS mutation will be passed to her offspring. However, the length and repeats in a male rarely

produce a full mutation (Hammer & McPhee, 2019, p. 19). A full mutation occurs when a

sequencing expands from premutation allele (55-200 repeats) to an allele containing >200

repeats (Dean et al., 2019).

When a premutation allele expands from 55-200 repeats to an amount greater than 200, it

causes a full mutation. This expansion causes the FMR1 gene to cease transcription and

methylation of the DNA located at the beginning of the FMR1 gene (Hammer & McPhee, 2019,

p. 19).

Clinical Manifestations

Clinical manifestations vary in correlation to the severity of the mutation and the gender

of the parent and offspring. In FXS, clinical manifestations are usually more severe in affected

males than in affected females.

Common clinical manifestations seen in patients with FXS are developmental and

intellectual delays, small joint hyperextensibility, hypotonia, macroorchidism, macrocephaly,

otapostasis, elongated face, and prominent facial features and usually do not start manifesting

themselves until the child enters their toddler years (Hammer & McPhee, 2019, p. 18).

Behavioral problems often have autism-like features and are seen more often in males than in

females (Ciaccio et al., 2017). Some of these behaviors are attention deficit, hand flapping,

biting, social isolation, and poor eye contact (Ricci, Kyle, & Carman, 2013).
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The clinical manifestations seen in FXS are caused by the ability of the FMR1 gene to

cease DNA methylation. DNA methylation is responsible for cell differentiation and tissue

development during early embryonic development and when turned off, cells are unable to

differentiate (Lanata, Chung, & Criswell, 2018). Lanata et al. (2018) further suggest:

“programming for various adverse health outcomes occurs [due to] disturbing DNA methylation

marks” (p. 4).

Mother is Carrier of the Genetic Mutation

As stated before, a father cannot pass the FXS mutation on to a son. Therefore, the

mother is the parent that passed the genetic mutation to her son. The mother is a carrier and not

an affected parent, as seen in the family history, which is unremarkable.

Phenotypical Unaffected Family Members

The FXS mutation is passed down through generations; at no time does the gene

ambiguously mutate. As the mutation is passed, the CGG repeat expands to become unstable

and develops into full mutations, which is known as penetrance (Hammer & McPhee, 2019).

People who carry premutations show no clinical manifestations of FXS. Therefore, the

gene mutation can be passed through generations without being detected until either a child or

grandchild presents with the clinical manifestations.

In the case of Ms. Anderson, it was determined she is a carrier. Since Ms. Anderson is a

female, the mutation could have been passed from either of her parents. If the mutation was

passed to her by her father, who shows no clinical manifestations, he would be among the 20%

of male carriers that have the premutation but show no signs (Hammer & McPhee, 2019, p. 17).
FRAGILE X SYNDROME 5

Chance the Unborn Child Will Be Affected

Based on the lack of significant family history, at this time, we do not know if the father

of the unborn child is the same father of the 3-year-old son. However, it has been determined

that the mother is the carrier of the FXS mutation. Since the mother is the carrier of the

mutation, the chance her unborn child will have FXS is 50%. The unborn child will either be

normal or affected, and there is no chance the unborn child will be a carrier of the FXS mutation

(Dean et al. 2019). If the unborn child is affected, the severity of clinical manifestations will

depend upon if it is a boy or girl. Research shows that boys with FXS usually have moderate to

severe developmental delays, with an IQ below 55; however, girl’s developmental delay is

usually less severe (Raspa, Wheeler, & Riley, 2017).

Fetal diagnostic testing for FXS is available through either amniocentesis or chorionic

villus sampling (CVS); furthermore, the gender of the fetus can be acquired at this time

(Gutierrez, Bajaj, & Klugman, 2013). These tests use methods that detect expansion and

methylation status that is used to determine the severity of FXS that will affect the unborn child

(Gutierrez, Bajaj, & Klugman, 2013).

References

Ciaccio, C., Fontana, L., Milani, D., Tabano, S., Miozzo, M., & Esposito, S. (2017). Fragile X

syndrome: A review of clinical and molecular diagnoses. Italian Journal of Pediatrics,

43(39). doi.org/10.1186/s13052-017-0355-y

Dean, D. D., Muthuswamy, S., & Agarwal, S. (2016). Fragile X syndrome: Current insight.

Egyptian Journal of Medical Human Genetics, 17(4), 303-309.

doi.org/10.1016/j.emhg.2016.01.005

Gurierrez, J. F., Bajaj, K., & Klugman, S. D. (2013). Prenatal screening for fragile X: Carriers,

controversies, and counseling. Reviews in Obstetrics & Gynecology 6(1), e1-e7.

Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651542/

Hammer, G. D. & McPhee, S. J. (2019). Genetic disease. Pathophysiology of disease: An

introduction to clinical medicine (8th ed., pp.17-20). New York, NY: McGraw Hill.

Lanata, C. M., Chung, S. A., & Criswell, A

(2018). DNA methylation 101: What is important to know about DNA methylation and its role

in SLE risk and disease heterogeneity. Lupus Science & Medicine Journal, 5(1).

doi:10.1136/lupus-2018-000285

Raspa, M., Wheeler, A. C., & Riley, C. (2017). Public health literature review of fragile X

syndrome. Journal of the American Academy of Pediatrics 139, (Supplement), S153-

S171. doi.org/10.1542/peds.2016-1159C

Ricci, S. S., Kyle, T., Carman, S. (2013). Maternity and pediatric nursing (2nd ed.).

Philadelphia, PA: Lippincott, Williams, & Wilkins.