Pitt-Hopkins Syndrome

Abstract

a Pitt-Hopkins-like phenotype has been assigned to autosomal recessive mutations of the CNTNAP2 gene at 7q33q36 and the NRXN1 gene at 2p16.3. Copyright © 2011 S. Karger AG, Basel History of the SyndromeIn 1978, pediatrician David Pitt and pediatric neurologist Ian Hopkins at the Royal Children's Hospital in Melbourne described 2 unrelated children with severe intellectual disability who while awake had spells of rapid overbreathing followed by holding of breath until cyanosis [Pitt and Hopkins, 1978]. Both patients had almost identical facial features with a wide mouth and palate, thick fleshy lips and a broad beaked nose with flared nostrils, and both also had clubbing of fingers and toes. The patients had been ascertained as a part of an etiological survey of 782 intellectually disabled individuals [Pitt and Roboz, 1965]. Over the next 28 years, only 4 sporadic patients [Singh 1993;Van Balkom et al., 1998;Peippo et al., 2006] and 1 pair of sibs [Orrico et al., 2001] supposed to have the same syndrome were published.In 2007, 2 independent groups using molecular karyotyping identified a microdeletion at 18q21.2 in 2 PittHopkins syndrome (PTHS) patients and subsequently haploinsufficiency of the TCF4 gene was found to cause the syndrome [Amiel et al., 2007;Zweier et al., 2007]. The original patients of Pitt and Hopkins [1978] and the one described by Singh [1993] were no longer available for Key WordsApnea ؒ Constipation ؒ Deletion of 18q ؒ Epilepsy ؒ Happy disposition ؒ Hyperpnea ؒ Myopia ؒ Pitt-Hopkins syndrome ؒ Stereotypic movements ؒ TCF4 Abstract Pitt-Hopkins syndrome (PTHS, MIM #610954) is characterized by severe intellectual disability, typical facial features and tendency to epilepsy, panting-and-holding breathing anomaly, stereotypic movements, constipation, and high myopia. Growth is normal or only mildly retarded, but half of the patients have postnatal microcephaly. Remarkably, congenital malformations are practically nonexistent. The cause of PTHS is de novo haploinsufficiency of the TCF4 gene (MIM * 602272) at 18q21.2. Altogether 78 PTHS patients with abnormalities of the TCF4 gene have been published since 2007 when the etiology of PTHS was revealed. In addition, 27 patients with 18q deletion encompassing the TCF4 gene but without given PTHS diagnosis have been published, and thus, the number of reported patients with a TCF4 abnormality exceeds 100. The mutational spectrum includes large chromosomal deletions encompassing the whole TCF4 gene, partial gene deletions, frameshift (including premature stop codon), nonsense, splice site, and missense mutations. So far, almost all patients have a private mutation and only 2 recurrent mutations are known. There is no evident genotype-phenotype correlation. No familial cases have been reported. Diagnosis of PTHS is based on the molecular confirmation of the characteristic clinical features. Recently,

Shining a light on CNTNAP2: complex functions to complex disorders

“…17,[49][50][51] PTHS is characterised by severe intellectual disability, absent or severely impaired speech, characteristic facial features and epilepsy. 52 Many of these features are shared with patients carrying CNTNAP2 mutations, leading researchers to test patients with PTHS-like features for CNTNAP2 mutations. 17 Two mutations affecting the CNTNAP2 locus (one homozygous and one compound heterozygote) were identified in two independent pedigrees (Table 1).…”

Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability

“…Following the identification of the gene, in excess of 120 molecularly confirmed cases of PTHS have been reported. In addition to the clinical features described by Pitt and Hopkins, developmental delay, stereotyped movements, absent speech and epilepsy are frequently found in PTHS patients [24,64]. Brain abnormalities such as agenesis or hypoplasia of the corpus callosum, decreased hippocampal volume and enlarged ventricles have been detected by magnetic resonance imaging (MRI) in approximately half of the cases examined [24].…”

“…Although epilepsy may be more common in PTHS patients with missense mutations, the disease phenotype seems remarkably similar across the mutational spectrum [24,[64][65][66]. Almost of all the TCF4 mutations that cause PTHS are predicted to disrupt transcripts encoding TCF4-A and TCF4-B.…”

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

“…Heterozygous deletions of TCF4 cause Pitt-Hopkins syndrome, a disorder of postnatal microcephaly, intellectual and speech delay, epilepsy and hyperventilation [Amiel et al, 2007;Brockschmidt et al, 2007;Zweier et al, 2007]. Also frameshift, nonsense, splice site, and missense mutations have been found in patients with Pitt-Hopkins syndrome [Peippo and Ignatius, 2012]. Mutations in the basic helix-loop-helix (bHLH) domain of TCF4 alter the subnuclear localization of the mutant protein and can attenuate homo-and heterodimer formation, whereas mutations proximal to the bHLH domain do not alter the location of TCF4 or impair heterodimer formation [Forrest et al, 2012].…”