title: The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.
abstract: 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.
authors.affiliation: Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marangi
authors.forename: Stefania
authors.initials: S
authors.lastname: Ricciardi
authors.forename: Daniela
authors.initials: D
authors.lastname: Orteschi
authors.forename: Serena
authors.initials: S
authors.lastname: Lattante
authors.forename: Marina
authors.initials: M
authors.lastname: Murdolo
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Chiara
authors.initials: C
authors.lastname: Biscione
authors.forename: Rosetta
authors.initials: R
authors.lastname: Lecce
authors.forename: Pietro
authors.initials: P
authors.lastname: Chiurazzi
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Donatella
authors.initials: D
authors.lastname: Greco
authors.forename: Rosa
authors.initials: R
authors.lastname: Pettinato
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorge
authors.forename: Chiara
authors.initials: C
authors.lastname: Pantaleoni
authors.forename: Enrico
authors.initials: E
authors.lastname: Alfei
authors.forename: Irene
authors.initials: I
authors.lastname: Toldo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Magnani
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonanni
authors.forename: Federica
authors.initials: F
authors.lastname: Martinez
authors.forename: Gigliola
authors.initials: G
authors.lastname: Serra
authors.forename: Domenica
authors.initials: D
authors.lastname: Battaglia
authors.forename: Donatella
authors.initials: D
authors.lastname: Lettori
authors.forename: Gessica
authors.initials: G
authors.lastname: Vasco
authors.forename: Anna
authors.initials: A
authors.lastname: Baroncini
authors.forename: Cecilia
authors.initials: C
authors.lastname: Daolio
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D019066:Facies; D005260:Female; D017353:Gene Deletion; D023061:Gene Order; D006801:Humans; D006985:Hyperventilation / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors