The CGG repeat that stacks, silences FMR1, and owns the boards when a boy has a long face, big ears, and hand-flapping before puberty.
Opening case: A 7-year-old boy is brought in for developmental evaluation. His teacher reports he avoids eye contact, flaps his hands when excited, and has difficulty keeping up with peers. On exam he has a long, narrow face and ears that protrude noticeably. What is the most likely underlying mutation?
Section 1 of 5
CGG repeats on the X chromosome, expanding across generations until the gene goes dark.
CGG REPEAT EXPANSION SPECTRUM
FMR1 gene active. FMRP protein produced. Synaptic signaling regulated normally.
Carrier state. Most carriers have normal intelligence. But the repeat is unstable and expands further when passed to offspring. See Sherman paradox below.
Repeat count reference
| Category | CGG repeats | Consequence |
|---|---|---|
| Normal | 5 to 54 | FMRP made normally |
| Premutation | 55 to 200 | Unstable; can expand. Carrier effects possible (POI, FXTAS) |
| Full mutation | >200 | Methylation silences FMR1 → zero FMRP → intellectual disability |
What is FMRP?
FMRP (Fragile X Mental Retardation Protein) is an RNA-binding protein whose job is to put the brakes on synaptic protein synthesis. At synapses, messenger RNAs pile up waiting to be translated. FMRP holds them in check, releasing them on demand when the synapse fires.
Without FMRP: proteins at the synapse are overproduced → synaptic signaling runs unchecked → intellectual disability, autism-like behavior, and seizures.
Think of it as a DJ controlling the volume: FMRP gone means the music never stops and blows out the speakers.
Sherman Paradox · Board Classic
A carrier grandmother (premutation, 55 to 200 CGG) passes the allele to her daughters, who are also carriers. Those daughters’ sons may receive an expanded allele that has crossed into full mutation (>200). This means later generations are more severely affected than earlier ones, which looks paradoxical until you understand anticipation via repeat expansion. The repeat only expands significantly through female meiosis.
Trinucleotide repeat comparison
| Disease | Repeat | Gene/Locus | Key clue |
|---|---|---|---|
| Fragile X | CGG | FMR1 (X chr) | Long face, macroorchidism |
| Huntington | CAG | HTT (4p) | Chorea, midlife onset |
| Myotonic dystrophy | CTG | DMPK | Grip myotonia, cataracts, frontal balding |
| Friedreich’s ataxia | GAA | FXN (9q) | Spinocerebellar ataxia, cardiomyopathy |
Section 2 of 5
Tap each card to reveal the clinical detail behind the clue.
The clue
Long, narrow, pill-shaped face. Forehead prominent. Jaw slightly prognathic. The elongation is present pre-puberty but becomes more pronounced after puberty. First board clue when combined with big ears.
The clue
Prominent, large, protruding ears. Not hearing loss; just structural. When you see “long face + big ears” in a child with ID, Fragile X is the answer before you see anything else.
The clue
Hand-flapping, avoidance of eye contact, echolalia (repeated phrases). FMRP controls mGluR5 signaling at the synapse. Without it, glutamate signaling goes haywire → autism spectrum behaviors. Fragile X is the most common single-gene cause of autism.
The clue
Moderate to severe ID in males (single X, no backup). Females with full mutation have milder ID because the normal X partially compensates. IQ range in affected males typically 20 to 70, mean around 40.
The clue
ADHD-like hyperactivity and attention problems are common. Often the presenting concern at school age. Overlaps with autism behaviors. Look for the physical exam findings (face, ears) to lock in Fragile X rather than primary ADHD.
The clue
Connective tissue laxity: joint hypermobility, flat feet. Some patients develop mitral valve prolapse (MVP). The FMRP protein influences connective tissue; its absence disrupts normal matrix signaling. Not as classic as the face/ears, but board-tested as a secondary finding.
Board logic · pre-puberty
The pre-puberty triad that locks it in: long face + big ears + autism-like behavior with ID. If all three are in the stem, write Fragile X before reading the choices.
Section 3 of 5
One finding changes everything. Tap to reveal it.
? The post-puberty clue ?
At puberty, one new physical finding emerges that is so specific it closes the diagnosis on the spot. What is it?
tap to reveal
Macroorchidism
Enlarged testicles. This is the #1 board clue post-puberty. Normal testis volume in adult males is approximately 15 to 25 mL. In Fragile X males the testes are typically 30 to 50 mL, visibly enlarged.
The mechanism: FMRP regulates FSH receptor signaling in Sertoli cells. Without FMRP, FSH-driven Sertoli cell proliferation goes unchecked during puberty → testicular enlargement. The testes are large but functionally impaired (reduced fertility is common).
Board rule: Intellectual disability + macroorchidism in a post-pubertal male = Fragile X, full stop.
Post-puberty #1
Macroorchidism
Emerges at puberty. Pathognomonic in context. Volume >30 mL. The board-locking clue.
Post-puberty #2
More elongated face
The already-long face grows narrower and longer. Jaw more prognathic. High-arched palate. Face + testes = game over.
Post-puberty #3
Persisting ID
Intellectual disability does not improve with age. Language remains limited. Many males are nonverbal or have severely limited speech.
Premutation carrier effects (board-tested)
Premature ovarian insufficiency (POI) · menopause before age 40. The premutation causes RNA toxicity in the ovary. Normal-ish intelligence but ovarian failure.
FXTAS (Fragile X-associated tremor/ataxia syndrome) · late-onset cerebellar ataxia and intention tremor. Affects men with premutation in their 60s+. Different from full mutation phenotype.
Section 4 of 5
X-linked, with a twist: repeat expansion means daughters can silently pass a worse allele to their sons.
Males are more severely affected (only one X = no backup). Females are often carriers with mild or no symptoms due to X-inactivation partially buffering the effect.
Each generation the CGG repeat gets longer. A grandmother with 80 repeats (premutation) can have a daughter with 120, whose son has >200 (full mutation). Severity increases generation by generation.
Repeat expansion occurs primarily through female meiosis. A premutation father passes a stable premutation (does not expand). This is why the Sherman paradox tracks through the maternal line.
Females with full mutation have variable phenotype: mild ID to normal IQ, depending on which X is preferentially inactivated in each tissue. Some have autistic features without significant ID.
Ranking clue · board favorite
#1 cause of inherited (chromosomal/monogenic) intellectual disability = Fragile X.
#2 cause of intellectual disability overall = Fragile X (fetal alcohol syndrome is #1 overall by sheer numbers). Both rankings are tested. Learn both answers for the same condition.
Section 5 of 5
Eight questions. Lock in the clues before you close the tab.