Pitt-Hopkins Syndrome

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].


Clinical characteristics: Pitt-Hopkins syndrome (PTHS) is characterized by significant developmental delays with moderate-to-severe intellectual disability and behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake. Speech is significantly delayed and most individuals are nonverbal with receptive language often stronger than expressive language. Other common findings are autism spectrum disorder symptoms, sleep disturbance, stereotypic hand movements, seizures, constipation, and severe myopia.

Diagnosis/testing: The diagnosis is suspected on clinical findings and confirmed by identification on molecular genetic testing of a heterozygous pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4 is located (18q21.2).

Management: Treatment of manifestations: Developmental services for infants (physical, occupational, and speech therapies); individualized education plan for older children with strong consideration for early training in alternative means of communication; behavioral management strategies; possible treatment of abnormal respiratory pattern. Routine management of seizures, myopia, constipation, scoliosis, and ankle instability.

Surveillance: Ongoing developmental assessments to tailor educational services to individual needs; regular follow up with an ophthalmologist to monitor for high myopia and strabismus; periodic reevaluation with a clinical genetics professional regarding current information and recommendations.

Genetic counseling: PTHS is caused by haploinsufficiency of TCF4 resulting from either a pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4 is located (18q21.2). Most affected individuals have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant or deletion. The risk to sibs of a proband is low, but higher than that of the general population because of the possibility of parental germline mosaicism. Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Publication types

  • Review