Pitt-Hopkins syndrome

Pitt-Hopkins syndrome is inherited in an autosomal dominant manner. Once the familial pathogenic variant has been identified, prenatal molecular testing is technically possible.

The diagnosis is clinically based and is guided by the international consensus statement on Pitt-Hopkins syndrome (Zollino et al., 2019); meeting these consensus criteria establishes the clinical diagnosis. Brain MRI is supportive but not diagnostic; common findings include hypoplasia or agenesis of the corpus callosum, white matter hyperintensity in the temporal poles, ventricular dilatation, and small hippocampi.

Main differential diagnoses include:

• : severely abnormal EEG, near-universal seizures, ataxia, and absence of the Pitt-Hopkins facial gestalt; UBE3A
• (classic): normal early development followed by regression of language and motor skills, primarily in females; MECP2
• : distinct facial gestalt with uplifted earlobes, hypertelorism, and frequent Hirschsprung disease; ZEB2

• Establishing the diagnosis: A confirmed molecular genetic diagnosis ends the diagnostic odyssey, supports prognostic counselling, and underpins all subsequent medical decisions.
• Specific and individualised clinical management: A confirmed molecular diagnosis is a prerequisite for targeted, individualised medical care, which is determined by the treating physicians in consultation with the affected individual and their family.
• Family member testing: Once the familial pathogenic variant has been identified, predictive testing of at-risk relatives and reproductive counselling become available.

• Sweetser DA, Gipson KS, Zar-Kessler C. Pitt-Hopkins Syndrome. 2025 May 22. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 22934316. Available from:
• Rosenfeld JA, Leppig K, Ballif BC, Thiese H, Erdie-Lalena C, Bawle E, et al. Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genetics in medicine : official journal of the American College of Medical Genetics. 2009;11(11):797-805. doi: 10.1097/GIM.0b013e3181bd38a9. PMID: .
• Zollino M, Zweier C, Van Balkom ID, Sweetser DA, Alaimo J, Bijlsma EK, et al. Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement. Clinical genetics. 2019;95(4):462-478. doi: 10.1111/cge.13506. PMID: .
• Goodspeed K, Newsom C, Morris MA, Powell C, Evans P, Golla S. Pitt-Hopkins Syndrome: A Review of Current Literature, Clinical Approach, and 23-Patient Case Series. Journal of child neurology. 2018;33(3):233-244. doi: 10.1177/0883073817750490. PMID: . PMCID: PMC5922265.