Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome

Giuseppe Marangi, Stefania Ricciardi, Daniela Orteschi, Romano Tenconi, Matteo Della Monica, Gioacchino Scarano, Domenica Battaglia, Donatella Lettori, Gessica Vasco, Marcella Zollino

Research output: Contribution to journalArticlepeer-review


Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation.

Original languageEnglish
Pages (from-to)1604-1611
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume158 A
Issue number7
Publication statusPublished - Jul 2012


  • Clinical Checklist
  • Pitt-Hopkins Syndrome
  • TCF4

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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