HEALTH WATCH TABLE — Fragile X Syndrome

Considerations

Recommendations

1. Head, eyes, ears, nose, throat
Children: Vision: strabismus, refractive errors are common Hearing: recurrent otitis media is common Nose: sinusitis is common	Undertake newborn vision and hearing screening and an auditory brainstem response (ABR) Refer for a comprehensive ophthalmologic examination by 4 years of age Visualize tympanic membranes at each visit
Adults: strabismus and refractive errors are common	Undertake hearing and vision screening at each visit with particular attention to myopia and hearing loss
2. Dental
Children and Adults: High arched palate and dental malocclusion are common	Refer to a dentist for a semi-annual exam
3. Cardiovascular
Children: Mitral valve prolapse (MVP) is less common in children (~10%) but may develop during adolescence	Auscultate for murmurs or clicks at each visit. If present, do an ECG and echocardiogram; refer to cardiologist, if indicated
Adults: MVP is common (~ 80%). Aortic root dilation usually is not progressive Hypertension is common and exacerbated by anxiety	Undertake an annual clinical exam. Based on findings, obtain an ECG and echocardiogram. Refer to cardiologist, as appropriate Measure BP at each visit and at least annually Treat hypertension when present
4. Sleep
Children and Adults: Obstructive sleep apnea (OSA) may be due to enlarged adenoids, hypotonia or connective tissue dysplasia Sleep apnea is more common in individuals with Fragile X-associated tremor/ataxia syndrome Children and Adults: Sleep-onset or sleep-maintenance insomnia is common	Ascertain a sleep history, examining bedtime, waketime, time needed to fall asleep and possible waking throughout the night Assess for evidence of OSA Refer to a sleep specialist, as appropriate Behavioral sleep interventions or supplemental melatonin may be helpful
5. Gastrointestinal
Children: In infants, feeding problems are common with recurrent emesis associated with Gastroesophageal Reflux Disease (GERD) in ~ 30% of infants	Refer for assessment of GERD. Thickened liquids and upright positioning may be sufficient to manage GERD
6. Genitourinary
Children and Adults: Inguinal hernias are relatively common in males Macroorchidism generally develops in late childhood and early adolescence and persists Ureteral reflux may persist into adulthood	Assess for inguinal hernia annually beginning at age 1 year Reassure patients and caregivers that macroorchidism does not require treatment Monitor for signs of urinary tract infections (UTI), screen with urinalysis. Evaluate recurring UTIs with cystourethrogram and renal ultrasound. Refer to a nephrologist. Consider and assess for a renal etiology, such as scarring, as the basis for persistent hypertension
7. Sexual function
Adults: Males and females are fertile	Consider discussion of recurrence risk and reproductive options as a basis for referral to a geneticist. Make such a referral even if Fragile X is only suspected so that molecular testing can be undertaken in the person concerned and relevant family members
8. Musculoskeletal (MSK)
Children & Adults: Hyperextensible joints and pes planus are common. Scoliosis, clubfeet, joint dislocations (particularly congenital hip) may also occur	Undertake an MSK exam at birth, then at each regularly scheduled checkup Elicit a history of possible dislocations Refer to an orthopedic surgeon as dictated by clinical findings Consider referral to a physical therapist (PT) or an occupational therapist (OT) to improve specific aspects of gross or fine motor skills if joint laxity or hypotonia interferes with function Consider referring to a physiotherapist and podiatrist for orthotics
9. Neurology
Children & Adults: ~ 20% have epilepsy (may include generalized tonic-clonic seizures, staring spells, partial motor seizures, and temporal lobe seizures) Hypotonia is common, in addition to fine and gross motor delays Epilepsy occasionally persists into adulthood	Ascertain a history of seizures, which usually present in early childhood Assess for atypical seizures in adulthood if suspicious findings occur or if intellectual function decreases Arrange an EEG if epilepsy is suspected from the history Refer to a neurologist as dictated by clinical findings
10. Behavioral/mental health
Children: 70% - 80% are hyperactive; ~ 30% have autism Autistic-like features are common and may indicate concurrent autism spectrum disorder Anxiety and mood disorders can also be present Some features of autism, tantrums and aggression as well as anxiety and mood disorders may be treated with specific pharmacological agents Sensory defensiveness is common and may trigger problem behaviors	Make an early referral to a clinical psychologist for essential parental teaching of appropriate behavior modification techniques following diagnosis Hyperactivity may be managed using stimulant medications after age 5 years Refer to an intensive behavioral intervention autism treatment program if autism spectrum disorder is present Consider a referral to a psychiatrist for possible mental health disorders Refer to a speech and language therapist following diagnosis
Adults: Aggressive behavior, sensory defensiveness, attention deficit hyperactivity disorder (ADHD), mood instability, and anxiety are common in adolescence and adulthood	Consider referral to a psychiatrist or psychologist to assess and manage possible mental health disorders Violent outbursts may occur, especially in males, and may respond to behavioral and/or pharmacological measures (as for children)
11. Endocrine
Children: Precocious puberty may occur	Include attention in clinical examination to signs of precocious puberty in females. Refer to an endocrinologist for consideration of use of a gonadotropin agonist to manage precocious puberty
Adults: Premenstrual symptoms (PMS) may be severe	Ascertain history of PMS with attention to menstruation, anxiety, depression, and mood lability. Consider an selective serotonin re-uptake inhibitor (SSRI) to stabilize mood if PMS symptoms are severe enough
12. Other
Occasionally presents as Prader-Willi syndrome-like phenotype Premutation Carriers: A late onset tremor/ataxia syndrome has been reported in ~ 40% – 50% of male and ~ 8% of female Fragile X permutation carriers Premature ovarian failure by age 45 has been reported in ~ 20% – 40% of female Fragile X permutation carriers Psychiatric problems (e.g., mood and anxiety disorders) seem likely to occur in both male and female Fragile X premutation carriers ^{1, 2}	For management of obesity and hyperphagia, consider approaches recommended for persons with Prader-Willi syndrome Refer to appropriate specialists (e.g., neurologist, endocrinologist, psychiatrist) as indicated to assist in managing Prader-Willi syndrome-like symptoms If premutation is suspected but not yet identified, order Fragile X DNA testing or refer to a genetics clinic To manage depression or anxiety in premutation carriers, SSRIs, regular exercise and counseling have been helpful

Original tool: ©2011 Surrey Place Centre.
Developed by Forster-Gibson C, Berg J, & Developmental Disabilities Primary Care Initiative Co-editors.

Expert Clinician Reviewers
Thanks to the following clinicians for the review and helpful suggestions.

Randi Hagerman, MD
Medical Director, M.I.N.D Institute
Endowed Chair in Fragile X Research, School of Medicine,
University of California, Davis, California
Carlo Paribello, MD
Director, Fragile X Clinic, Surrey Place Centre, Toronto
President and Medical Director, Fragile X Research Foundation of Canada

Modified with permission of Surrey Place Centre. This tool was reviewed and adapted for U.S. use by physicians on the Toolkit’s Advisory Committee; for list, view here.

Additional reviewer was Jeremy M. Veenstra-VanderWeele, M.D., Assistant Professor of Psychiatry, Pediatrics, and Pharmacology; Medical Director, Treatment and Research Institute for Autism Spectrum Disorders (TRIAD); Director, Fragile X Treatment Research Program; Director, Division of Child and Adolescent Psychiatry, Vanderbilt University, Nashville.

Resources

8 published Fragile X syndrome health care guidelines reviewed and compared (For full list of references, see http://ddprimarycare.surreyplace.ca/wp-content/uploads/2018/03/HWT_Fragile-X.pdf) Accessed July 2021.
Fragile X syndrome websites that may be helpful for families and caregivers
- FRAXA Research Foundation
  www.fraxa.org. Accessed July 2021.
- The National Fragile X Foundation
  www.fragilex.org. Accessed July 2021.
- Fragile X Research Foundation of Canada
  www.fragilexcanada.ca/index.php?home&lng=en. Accessed July 2021.

References

Amiri K, Hagerman RJ, Hagerman PJ. Fragile X-associated tremor/ataxia syndrome: an aging face of the fragile X gene. Arch Neurol 2008 Jan;65(1):19-25.
Bourgeois JA, Coffey SM, Rivera SM, Hessl D, Gane LW, Tassone F, et al. A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 2009 Jun;70(6):852-62.

HEALTH WATCH TABLE — Fragile X Syndrome

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