AAP Health Supervision for Children with Fragile X Syndrome

Question 1

What is the genetic inheritance for Fragile X?

Answer 1

FMR1 gene with trinucleotide repeat (CGG)
>200 full mutation
55-200 premutation
45-54 intermediate or “gray-zone” alleles
5-40 normal

Question 2

What is the clinical phenotype for males with fragile X?

Answer 2

1. Developmental delay
2. Mental retardation
3. Prominent forehead
4. Long, narrow face
5. Prominent jaw
6. Protruberant ears
7. High arched palate
8. Cleft palate
9. Dental crowding
10. Malocclusion
11. Strabismus (23-50% refractive errors)
12. Nystagmus
13. Ptosis
14. Macro-orchidism ~80% adolescents
15. Connective tissue dysplasia:
    a) soft velvet-like skin
    b) joint hypermobility esp. fingers
    c) pes planus
    d) congenital hip dislocation
    e) scoliosis
    f) clubfoot
    g) mitral valve prolapse in adults
16. GER (1/3 of infants)
17. Chronic otitis media 60-80%
18. Recurrent otitis media 23%
19. Seizures ~13-18%
20. Relative macrocephaly
21. Tall stature in childhood
22. Subgroup “Prader-Willi syndrome clinical phenotype”: extreme obesity, short stature, stubby hands and feet, diffuse hyperpigmentation
23. Mental retardation
24. Cognitive deficits
25. Language delay
26. ADHD 80%
27. Anxiety incld. OCD
28. Emotional lability
29. Aggressive and self-injurious behaviors
30. Hypersensitivity to sensory stimuli
31. Autism features, 30% with full mutation have
32. Premature ovarian insufficiency in females with premutation
33. FXTAS - ataxia in 50s of males with premutation

Question 3

Who should have molecular genetic testing by PCR and/or southern blot analysis for FMR1?

Answer 3

1. Patient with family history of fragile X syndrome
2. Males and females >50yo with progressive cerebellar ataxia and intention tremor
3. Patients with developmental delay, intellectual disability of unknown etiology or autism
4. Females with premature ovarian insufficiency (POI)

Question 4

What should occur during the prenatal visit for Fragile X syndrome?

Answer 4

1. Review the diagnostic studies that led to establishment of the diagnosis
2. Explain the clinical manifestations, the variability seen in fragile X syndrome and the long term prognosis
3. Review the clinical manifestations, the variability seen in fragile X syndrome, and the long-term prognosis
4. Review currently available treatments and interventions
5. Explore options (termination, rearing at home, foster care, adoption)

Question 5

What are the health supervision guidelines for newborns with Fragile X (birth to 1mo)?

Answer 5

1. Examine the neonate for any orthopedic abnormalities, esp. congenital hip dysplasia and clubfoot
2. Review molecular testing with the family
3. Review clinical manifestations
4. Monitor OFC and monitor head growth velocity
5. Monitor for feeding difficulties and symptoms of GER

Question 6

What anticipatory guidance is recommended for newborns with Fragile X (birth to 1mo)?

Answer 6

1. Review the support groups and services available
2. Discuss resources available for personal support
3. Discuss how and what to tell family members and friends about the neonate’s condition
4. Review the recurrence risk for subsequent pregnancies
5. Discuss options for family planning and genetic counselling
6. Review the family history for other family members at risk of Fragile X

Question 7

What are the health supervision guidelines during infancy for Fragile X (1mo to 1yo)?

Answer 7

1. Monitor for hypotonia and mild motor delay
2. Monitor for irritability, which is usu. secondary to sensory problems incld. tactile hypersensitvity
3. Monitor for feeding problems, esp. GER

Question 8

What anticipatory guidance are recommended for infants (1mo to 1yo) with Fragile X?

Answer 8

1. Monitor growth parameters closely
2. Pursue diagnostic evaluation if feeding problems are severe
3. Review available resources to provide the infant with early-intervention services

Question 9

What are the health supervision guidelines for Fragile X in early childhood (1-5yo)?

Answer 9

1. Ophthalmology evaluation for strabismus and refractive errors
2. Evaluate child for orthopedic problems related to connective tissue dysplasia esp. pes planus (80% affected children), hypermobile joints, and scoliosis
3. Treat pronated feet require treatment with orthotics if gait disturbance exists
4. Examine the child for inguinal hernias esp. @1-3yo
5. Assess the child’s history for seizures or staring episodes and obtain an EEG if clinically indicated
6. Monitor the child for recurrent otitis media (60-80%) could be associated with conductive hearing loss, also for recurrent sinusitis (23%)
7. Monitor child’s audiologic status yearly
8. Monitor language closely
9. OT evaluation as indicated
10. IQ testing
11. Requires early developmental services
12. Monitor child’s emotional and behavioral status closely and provide interventions as needed
13. Psychopharmacologic interventions can be helpful
    - consider stimulant medication, clonidine, guanfacine, SSRI, atypical antipsychotics
14. Monitor linear growth (should be normal)
15. Monitor for facial changes and regular dental evaluations recommended
16. Monitor OSA
17. Delayed toilet training is common and likely to reflect the child’s cognitive status

Question 10

What anticipatory guidance should be provided for patients with Fragile X in early childhood (1-5yo)?

Answer 10

1. Determine if behaviors such as hyperactivity, aggression, self-injury, and tantrums warrant medical management
2. Appropriate evaluation and treatment is indicated when suspicion of seizure if present
3. Monitor for murmurs, clicks, and BP and provide medical treatment as indicated
4. Delays in toilet-training help with behavioral interventions
5. Review the future reproductive plans for the parents and discuss recurrence risk and family planning options when indicated

Question 11

What are the health supervision guidelines for Fragile X in late childhood (5-12yo)?

Answer 11

1. Measure testicular volume with orchidiometer and assess for presence of hernia
2. Monitor for precocious puberty in girls with full mutation
3. Monitor for cognitive, speech, language, and motor needs and modifications or further evaluation are indicated
   4, Monitor ADHD and address behaviorally and/or in combination with medication management
4. Monitor for anxiety, esp. OCD and appropriate management
5. Monitor for cognitive impairments and provide appropriate services
6. Enuresis is common –> manage appropriately
7. Monitor for scoliosis due to connective tissue dysplasia (~20%)

Question 12

What are the health supervision guidelines for Fragile X in adolescent to early adulthood (13-21yo)?

Answer 12

1. Attentional problems and impulsivity frequently persist and may continue to need to be addressed behaviorally and medically
2. Assess adolescents for seizures esp. atypical
3. Reassure that macro-orchidism will persist but are fertile
4. Monitor for growth, psychosocial development, physical sexual development, and fertility
5. Discuss genetic mechanisms responsible for fragile X syndrome
6. Determine if behavioral problems continue to represent a concern, and pursue behavioral/psychological intervention if indicated
7. Discuss the availability and need for vocational training and group home placement if appropriate
8. Monitor for a cardiac murmur or click, if either is heard pursue a cardiology evaluation
9. Facilitate transition to adult medical care as appropriate or desired

Question 13

What are the health supervision guidelines for Fragile X in adulthood?

Answer 13

1. Mitral valve prolapse (~50% affected adults) with mild aortic root dilatation
2. Monitor for hypertension
3. Greater risk of emotional problems in affected females, esp. at times of hormonal changes or estrogen deficiency, such as menopause, the postpartum period and during menstrual periods
4. Genetic counseling and review for risks of transmission
5. Risk of FXTAS >50yo in men>women with premutation