Pitt-Hopkins syndrome
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A child with severe intellectual disability and absent speech has episodes of hyperventilation followed by apnea. He has a distinctive happy demeanor and wide mouth with widely spaced teeth.
AD (de novo); TCF4 gene
- Severe intellectual disability, absent/minimal speech
- Distinctive facies: wide mouth, cupid's bow upper lip, widely spaced teeth
- Breathing abnormalities (hyperventilation/apnea episodes)
- Happy demeanor (similar to Angelman)
- Constipation, myopia
- Clinical suspicion from severe intellectual disability, absent speech, and episodic hyperventilation/apnea with the distinctive facies
- Molecular confirmation by TCF4 sequencing and deletion/duplication analysis (most variants are de novo)
- Consider testing for Angelman-overlap conditions (UBE3A, methylation) and CNTNAP2/NRXN1 when TCF4 is negative
- Developmental support: speech, occupational, and physical therapy; augmentative communication
- Antiseizure medication for epilepsy; manage breathing episodes and evaluate for apnea
- Aggressive constipation management; ophthalmology follow-up for myopia and strabismus
- Genetic counseling: typically de novo with low recurrence risk (germline mosaicism reported)
"Brad Pitt + Angelina Jolie": Just like Brad (Pitt-Hopkins) and Angelina (Angelman) are a famous pair, these two syndromes look alike: both have happy demeanor, absent/minimal speech, and seizures. To tell them apart: Brad = Breathing episodes (hyperventilation/apnea), which are unique to Pitt-Hopkins. Jolie = Jolly, since the happy demeanor is prominent in both. Gene: TCF4 causes Pitt-Hopkins (vs UBE3A in Angelman).