Further delineation of Pitt-Hopkins syndrome: Phenotypic and genotypic description of 16 novel patients

Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Journal of Medical Genetics (Impact Factor: 6.34). 09/2008; 45(11):738-44. DOI: 10.1136/jmg.2008.060129
Source: PubMed


Haploinsufficiency of the gene encoding for transcription factor 4 (TCF4) was recently identified as the underlying cause of Pitt-Hopkins syndrome (PTHS), an underdiagnosed mental-retardation syndrome characterised by a distinct facial gestalt, breathing anomalies and severe mental retardation.
TCF4 mutational analysis was performed in 117 patients with PTHS-like features.
In total, 16 novel mutations were identified. All of these proven patients were severely mentally retarded and showed a distinct facial gestalt. In addition, 56% had breathing anomalies, 56% had microcephaly, 38% had seizures and 44% had MRI anomalies.
This study provides further evidence of the mutational and clinical spectrum of PTHS and confirms its important role in the differential diagnosis of severe mental retardation.

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    • "Subsequent independent reports confirmed the initial clinical spectrum as a distinct entity and led to the formalization of a disorder thereafter referred to in the literature by the name ‘Pitt–Hopkins Syndrome'.3, 4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 PTHS is extremely rare and, as of this writing, approximately 200–300 diagnosed cases are known to exist worldwide.30, 31, 32 Thus, PTHS falls in the category of an ‘ultra-orphan' disease for purposes of FDA (Food and Drug Administration) approval for novel therapies under the Orphan Drug Act of 1983, and in some cases special funding programs for orphan disease patient treatment is available through government, biotech and pharmaceutical industry programs. "
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    ABSTRACT: TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt-Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.
    05/2013; 45(5):e21. DOI:10.1038/emm.2013.32
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    • "Zweier et al. showed that HSCR in patients with PHS might be explained by altered development of noradrenergic derivatives (Zweier et al., 2007). They thought haploinsufficiency as the disease-causing mechanism (Zweier et al., 2008). Today, mutations in more than 11 different genes have been implicated in the pathogenesis of HSCR (Table 1). "
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    ABSTRACT: Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system, which occurs due to the failure of neural crest cells to fully colonize the gut during embryonic development. It is characterized by the absence of the enteric ganglia in a variable length of the intestine. Substantial progress has been made in understanding the genetic basis of HSCR with the help of advanced genetic analysis techniques and animal models. More than 11 genes have been found to be involved in the pathogenesis of HSCR. The RET gene is the most important susceptibility gene involved in HSCR with both coding and non- coding sequence mutations. Due to phenotypic diversity and genetic complexity observed in HSCR, mutational analysis has limited practical value in genetic counseling and clinical practice. In this review, we discuss the progress that has been made in understanding the molecular genetics of HSCR and summarize the currently identified genes as well as interactions between pathways and gene-modifying loci in HSCR. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 10/2012; 295(10):1628-38. DOI:10.1002/ar.22538 · 1.54 Impact Factor
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    • "Scoliosis is reported in more than one tenth of the individuals , but none of the published cases are known to have needed orthopedic measures to treat it. Only 2 individuals had gastroesophageal reflux [Giurgea et al., 2008] and one had pyloric stenosis [Zweier et al., 2008]. A frequent ailment is severe constipation, but only one patient had Hirschsprung disease [Peippo et al., 2006]. "
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    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, 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.
    Molecular syndromology 04/2012; 2(3-5):171-180. DOI:10.1159/000335287
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