Fragile X Syndrome

Question 1

What type of genetic disorder is Fragile X?

Answer 1

Trinucleotide repeat CGG FMR1 gene

Question 2

How many repeats does a normal individual have?

Answer 2

5-44

Question 3

How many repeats is the intermediate grey zone?

Answer 3

45-54

Question 4

How many repeats does a premutation carrier have?

Answer 4

55-200

Question 5

How many repeats does a full mutation have?

Answer 5

> 200

Question 6

What occurs when maternal premutation carrier transmits to offspring?

Answer 6

Unstable FMR1 allele expands to full mutation >200 repeats

Question 7

What are associated medical findings?

Answer 7

1. Mild overgrowth
2. Mild macrocephaly
3. Feeding problems esp. colic
4. Seizures 20%
5. Strabismus, hyperopia
6. Recurrent OM and sinus infections
7. Mitral valve prolapse
8. Macroorchidism (80-90%)
9. Joint hyperlaxity - pes planus
10. Occasional pectus deformity
11. Long face, high forehead, high arched palate, prominent ears, dental crowding

Question 8

What are the associated developmental outcomes?

Answer 8

1. Mild motor delays are common: Hypotonia, hyperextensibility
2. Sensory integration problems and irritability may be seen
3. Infants may be colicky, toddlers irritable – rigid with difficulty during transitions
4. Language delays; cluttered speech
5. Stereotypies and other common autistic behaviors: Poor eye contact, social anxiety
6. Intellectual disability
   a) Average IQ of 41 for fully affected adult male
   b) Average IQ 88 for higher functioning males
   c) Average range of 70-84 for females with the full mutation
7. Hyperactivity is common and improve with age
8. Enuresis is common
9. Carrier females can also be affected

Question 9

What is the DDx for Fragile X?

Answer 9

1. ADHD, LD, Autism
2. Intellectual disability
3. Hearing Loss, Visual Impairment
4. Several X-linked disability disorders incld. Lujan-Fryns Syndrome (marfanoid habitus and macroorchidism) and Atkin syndrome (large ears, macroorchidism, short statur)
5. Sotos Syndrome (cerebral gigantism): overgrowth syndrome with features of macrocephaly, prominent forehead, prominent chin/mandible, coordination dysfunction, usu. intellectual disability and difficult behavior

Question 10

What are the health supervision recommendations for Fragile X?

Answer 10

1. Echocardiogram
2. Developmental Evaluation/School Supports
3. Consider family member carrier testing

Question 11

What are the major clinical manifestations of Fragile X?

Answer 11

1. MR (moderate to severe)
2. Possible autism
3. Macro-orchidism (post pubertal)
4. Long face, large ears, large jaw