Fetal pads as a clue to the diagnosis of Pitt–Hopkins syndrome

Lehalle, Daphné; Williams, Charles A.; Siu, Victoria Mok; Clayton‐Smith, Jill

doi:10.1002/ajmg.a.34055

Cited by 16 publications

(21 citation statements)

References 46 publications

(49 reference statements)

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“…Surprisingly, prominent macroscopic brain abnormalities are not common in PTHS: only subtle hypoplasia of the corpus calossum has been consistently reported [139][140][141], while also enlarged ventricles (similar to schizophrenia, [142] and thin hindbrain [140,141] as well as enlarged caudate nuclei and a lower hippocampus volume have been reported [143]. Whalen et al estimated that only about 50% of the PTHS patients display abnormalities in structural brain imaging, while only about…”

Section: Tcf4 and Neurodevelopmental Disordersmentioning

confidence: 99%

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Quednow

Brzózka

Rossner

2014

Cell. Mol. Life Sci.

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Schizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits. Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4). Haploinsufficiency of the TCF4 (formatting follows IUPAC nomenclature: TCF4 protein/protein function, Tcf4 rodent gene cDNA mRNA, TCF4 human gene cDNA mRNA) gene causes the Pitt-Hopkins syndrome-a neurodevelopmental disease characterized by severe mental retardation. Accordingly, Tcf4 null-mutant mice display developmental brain defects. TCF4-associated risk alleles are located in putative coding and non-coding regions of the gene. Hence, subtle changes at the level of gene expression might be relevant for the etiopathology of schizophrenia. Behavioural phenotypes obtained with a mouse model of slightly increased gene dosage and electrophysiological investigations with human risk-allele carriers revealed an overlapping spectrum of schizophrenia-relevant endophenotypes. Most prominently, early information processing and higher cognitive functions appear to be associated with TCF4 risk genotypes. Moreover, a recent human study unravelled gene × environment interactions between TCF4 risk alleles and smoking behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental, and, possibly, plasticity-related transcriptional programs in the CNS and changes of TCF4 expression also appear to affect brain networks important for information processing. Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis for identifying the underlying molecular mechanisms. AbstractSchizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits.Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4 behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental and possibly also plasticity related transcriptional programs in the CNS and changes of TCF4 expression appear to affect brain networks important for information processing.Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis to identify the und...

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Section: Tcf4 and Neurodevelopmental Disordersmentioning

confidence: 99%

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Quednow

Brzózka

Rossner

2014

Cell. Mol. Life Sci.

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“…observation and this might turn out to be a useful additional diagnostic sign [Lehalle et al, 2011]. A constant feature of PTHS is severe intellectual disability.…”

Section: Clinical Descriptionmentioning

confidence: 99%

“…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].…”

Section: Clinical Descriptionmentioning

confidence: 99%

“…Altogether 78 PTHS patients with alterations in the TCF4 gene have been published (summarized in Marangi et al [2011]; in addition, 1 patient in Hasi et al [2011]; and 2 patients in Lehalle et al [2011]). Of these, 18 are chromosome deletions encompassing the whole TCF4 gene, 6 partial gene deletions, 25 frameshift mutations including premature stop codons, 7 nonsense mutations, 5 splice site mutations, and 17 missense mutations.…”

Section: Mutation Spectrum and Genotype-phenotype Correlationmentioning

confidence: 99%

“…Many PTHS patients have been ascertained through TCF4 gene analysis in children with unsteady gait, lack of speech and happy disposition but who had normal results in Angelman syndrome 15q11.2 methylation test and UBE3A mutation analysis [Takano et al, 2010;Lehalle et al, 2011]. Takano et al [2010] detected 2% PTHS patients among those who had a negative result in Angelman syndrome testing.…”

Section: Differential Diagnosismentioning

confidence: 99%

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Pitt-Hopkins Syndrome

Peippo

Ignatius

2011

Mol Syndromol

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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,

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