Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Mar;33(3):233-244.
doi: 10.1177/0883073817750490. Epub 2018 Jan 10.

Pitt-Hopkins Syndrome: A Review of Current Literature, Clinical Approach, and 23-Patient Case Series

Kimberly Goodspeed  1   2 , Cassandra Newsom  1   2 , Mary Ann Morris  2 , Craig Powell  1 , Patricia Evans  1   2 , Sailaja Golla  1   2
Affiliations
Review

Pitt-Hopkins Syndrome: A Review of Current Literature, Clinical Approach, and 23-Patient Case Series

Kimberly Goodspeed et al. J Child Neurol. 2018 Mar.

Abstract

Pitt-Hopkins syndrome (PTHS) is a rare, genetic disorder caused by a molecular variant of TCF4 which is involved in embryologic neuronal differentiation. PTHS is characterized by syndromic facies, psychomotor delay, and intellectual disability. Other associated features include early-onset myopia, seizures, constipation, and hyperventilation-apneic spells. Many also meet criteria for autism spectrum disorder. Here the authors present a series of 23 PTHS patients with molecularly confirmed TCF4 variants and describe 3 unique individuals. The first carries a small deletion but does not exhibit the typical facial features nor the typical pattern of developmental delay. The second exhibits typical facial features, but has attained more advanced motor and verbal skills than other reported cases to date. The third displays typical features of PTHS, however inherited a large chromosomal duplication involving TCF4 from his unaffected father with somatic mosaicism. To the authors' knowledge, this is the first chromosomal duplication case reported to date.

Keywords: autism; behavior; developmental delay; genetics; intellectual disability; ophthalmology; pediatric; seizures.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Graph depicting the rates of commonly reported dysmorphic characteristics as reported in the published cases.
Figure 2
Figure 2
Photographs demonstrating the facial gestalt commonly seen in PTHS: broad nasal bridge with bulbous tip, wide mouth with Cupid’s bow philtrum, and prominent ears.
Figure 3
Figure 3
Photographs demonstrating the fetal pads, flat feet, and overriding toes.
Figure 4
Figure 4
Graph depicting rates of the neurodevelopmental and behavioral traits described in the published cases.
Figure 5
Figure 5
Graph depicting the rates of the associated gastroenterological and ophthalmologic disorders commonly reported in published cases of PTHS.
Figure 6
Figure 6
Sagittal T1 MRI scans (left) and axial T2 (top right) and FLAIR (bottom right) MRI Scans depicting common anomalies seen in PTHS including dysplasia of the corpus callosum, bulging caudate, global atrophy, and scattered T2 hyperintensities. Images are from our cohort at UTSW Medical Center / Children’s Health Center for Autism and Developmental Disabilities.
Figure 7
Figure 7
Graph depicting the rates of common clinical findings in our cohort of PTHS patients compared to the rates of previously published cases. GDD – global developmental delay
See this image and copyright information in PMC

References

    1. Amiel J, Rio M, de Pontual L, et al. Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am J Hum Genet. 2007;80(5):988–93. - PMC - PubMed
    1. Brockschmidt A, Todt U, Ryu S, et al. Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum Mol Genet. 2007;16(12):1488–94. - PubMed
    1. Zweier C, Peippo MM, Hoyer J, et al. Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome) Am J Hum Genet. 2007;80(5):994–1001. - PMC - PubMed
    1. Sweatt JD. Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp Mol Med. 2013;45:e21. - PMC - PubMed
    1. Pitt D, Hopkins I. A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust Paediatr J. 1978;14(3):182–4. - PubMed

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources