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.

Development, cognition, and behaviour in Pitt–Hopkins syndrome

“…Behaviour will also be influenced by interactions within social and learning environments and by reactions from that environment to the individual's tempera- [6][7][8][9][10][11]13,14,[30][31][32][33][34][35] Published cases with proven TCF4 mutations [6][7][8][9][10][11]13,14,[30][31][32][33][34][35] Present study ment, external features, and neuropsychological deficits. Studying phenotypes of rare and ultra-rare genetic syndromes associated with severe intellectual disability has made it clear that, although individual outcomes may arise from genetic differences, the expression of genes affecting structure, development and function of the brain is also influenced by the interplay between genes, learning, and social context, and too much emphasis on biological determinants should be avoided.…”

“…The dominant form of PTHS is caused by deletions ⁄ mutations in Transcription Factor 4 (TCF4) on chromosome 18 at 18q21. [6][7][8][9][10][11][12][13][14] Recessive forms of a PTHS-like disorder are caused by mutations in NeuReXiN1 (NRXN1) on chromosome 2 and CoNTactiN Associated Protein-like 2 (CNT-NAP2) on chromosome 7. 15,16 As studies of the syndrome have accumulated, it has become clear that not all individuals with molecularly confirmed alterations show intermittent overbreathing.…”

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

“…Individuals with PHS may have clubbing of the fingertips whereas in the CDKL5 disorder the distal phalanges are relatively narrow and/or short. 45 In classical RTT no typical facial gestalt has been described, although some clinicians have suggested a facial similarity to Angelman syndrome. 46 A recent study using a combination of measurement and subjective impression found the only distinctive facial profile difference in RTT was a relatively broad upper face, especially in girls o3 years old.…”

Pitt-Hopkins Syndrome

“…Only one patient with congenital microcephaly with OFC ! 3rd centile at birth has been published [Marangi et al, 2011]. Growth retardation is later seen in a quarter of the patients.…”

“…features and major types of TCF4 gene mutations found in 77 molecularly confirmed patients aged 11 months to 29 years [Peippo et al, 2006;Amiel et al, 2007;Brockschmidt et al, 2007;Zweier et al, 2007Zweier et al, , 2008Zweier et al, , 2009Andrieux et al, 2008;Giurgea et al, 2008;de Pontual et al, 2009;Rosenfeld et al, 2009;Kato et al, 2010;Taddeucci et al, 2010;Takano et al, 2010;Stavropoulos et al, 2010;Lehalle et al, 2011;Marangi et al, 2011].…”