The Pitt-Hopkins syndrome: Report of 16 new patients and clinical diagnostic criteria

Giuseppe Marangi, Stefania Ricciardi, Daniela Orteschi, Serena Lattante, Marina Murdolo, Bruno Dallapiccola, Chiara Biscione, Rosetta Lecce, Pietro Chiurazzi, Corrado Romano, Donatella Greco, Rosa Pettinato, Giovanni Sorge, Chiara Pantaleoni, Enrico Alfei, Irene Toldo, Cinzia Magnani, Paolo Bonanni, Federica Martinez, Gigliola SerraDomenica Battaglia, Donatella Lettori, Gessica Vasco, Anna Baroncini, Cecilia Daolio, Marcella Zollino

Research output: Contribution to journalArticlepeer-review


Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin.

Original languageEnglish
Pages (from-to)1536-1545
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Issue number7
Publication statusPublished - Jul 2011


  • Balanced translocation
  • Haploinsufficiency
  • Pitt-Hopkins syndrome
  • TCF4

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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