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Genetics Home Reference: your guide to understanding genetic conditions
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Pitt-Hopkins syndrome

Reviewed May 2011

What is Pitt-Hopkins syndrome?

Pitt-Hopkins syndrome is a condition characterized by intellectual disability and developmental delay which range from moderate to severe, breathing problems, recurrent seizures (epilepsy), and distinctive facial features.

People with Pitt-Hopkins syndrome have severe intellectual disability and developmental delay. Most affected individuals do not learn to walk unassisted. People with this condition typically do not develop speech; some may learn to say a few words.

Breathing problems in individuals with Pitt-Hopkins syndrome are characterized by episodes of rapid breathing (hyperventilation) followed by periods in which breathing slows or stops (apnea). These episodes can cause a lack of oxygen in the blood, leading to a bluish appearance of the skin or lips (cyanosis). In some cases, the lack of oxygen can cause loss of consciousness. Some older individuals with Pitt-Hopkins syndrome develop widened and rounded tips of the fingers and toes (clubbing) because of recurrent episodes of decreased oxygen in the blood. The breathing problems occur only when the person is awake and typically first appear within the first decade of life; they can begin as early as infancy. Episodes of hyperventilation and apnea can be triggered by emotions such as excitement or anxiety or by extreme tiredness (fatigue).

Epilepsy occurs in most people with Pitt-Hopkins syndrome and usually begins during childhood, although it can be present from birth.

Individuals with Pitt-Hopkins syndrome have distinctive facial features that include thin eyebrows, sunken eyes, a prominent nose with a high nasal bridge, a pronounced double curve of the upper lip (Cupid's bow), a wide mouth with full lips, and widely spaced teeth. The ears are usually thick and cup-shaped.

Children with Pitt-Hopkins syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements. However, they can also experience anxiety and behavioral problems.

Other features of Pitt-Hopkins syndrome may include constipation and other gastrointestinal problems, small hands and feet, a single crease across the palms of the hands, flat feet (pes planus), an unusually small head (microcephaly), nearsightedness (myopia), eyes that do not look in the same direction (strabismus), short stature, and minor brain abnormalities. Males with Pitt-Hopkins syndrome may have an unusually small penis or undescended testes (cryptorchidism).

How common is Pitt-Hopkins syndrome?

Pitt-Hopkins syndrome is thought to be a rare condition. At least 50 affected individuals have been reported worldwide.

What genes are related to Pitt-Hopkins syndrome?

Mutations in the TCF4 gene cause Pitt-Hopkins syndrome. This gene provides instructions for making a protein that attaches (binds) to other proteins and then binds to specific regions of DNA to help control the activity of many other genes. On the basis of its DNA binding and gene controlling activities, the TCF4 protein is known as a transcription factor. The TCF4 protein plays a role in the maturation of cells to carry out specific functions (cell differentiation) and the self-destruction of cells (apoptosis).

TCF4 gene mutations disrupt the protein's ability to bind to DNA and control the activity of certain genes. These disruptions, particularly the inability of the TCF4 protein to control the activity of genes involved in nervous system development and function, contribute to the signs and symptoms of Pitt-Hopkins syndrome. Furthermore, additional proteins interact with the TCF4 protein to carry out specific functions. When the TCF4 protein is nonfunctional, these other proteins are also unable to function normally. It is also likely that the loss of the normal proteins that are attached to the nonfunctional TCF4 proteins contribute to the features of this condition. The loss of one protein in particular, the ASCL1 protein, is thought to be associated with breathing problems in people with Pitt-Hopkins syndrome.

Related Gene(s)

Changes in this gene are associated with Pitt-Hopkins syndrome.

  • TCF4

How do people inherit Pitt-Hopkins syndrome?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Most cases of this condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

Where can I find information about diagnosis or management of Pitt-Hopkins syndrome?

These resources address the diagnosis or management of Pitt-Hopkins syndrome and may include treatment providers.

  • Gene Review: Pitt-Hopkins Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK100240)
  • Genetic Testing Registry: Pitt-Hopkins syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1970431)

You might also find information on the diagnosis or management of Pitt-Hopkins syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/pitt-hopkins-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/pitt-hopkins-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Pitt-Hopkins syndrome?

You may find the following resources about Pitt-Hopkins syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Pitt-Hopkins syndrome?

  • PHS
  • PTHS

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Pitt-Hopkins syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Pitt-Hopkins syndrome?

anxiety ; apnea ; apoptosis ; autosomal ; autosomal dominant ; cell ; constipation ; cryptorchidism ; cyanosis ; developmental delay ; differentiation ; disability ; DNA ; embryonic ; epilepsy ; gastrointestinal ; gene ; inherited ; microcephaly ; myopia ; nearsightedness ; nervous system ; oxygen ; protein ; reproductive cells ; short stature ; sperm ; stature ; strabismus ; syndrome ; testes ; transcription ; transcription factor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, Plouin P, Carter NP, Lyonnet S, Munnich A, Colleaux L. 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 May;80(5):988-93. Epub 2007 Mar 23. (http://www.ncbi.nlm.nih.gov/pubmed/17436254?dopt=Abstract)
  • Brockschmidt A, Todt U, Ryu S, Hoischen A, Landwehr C, Birnbaum S, Frenck W, Radlwimmer B, Lichter P, Engels H, Driever W, Kubisch C, Weber RG. Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum Mol Genet. 2007 Jun 15;16(12):1488-94. Epub 2007 May 3. (http://www.ncbi.nlm.nih.gov/pubmed/17478476?dopt=Abstract)
  • de Pontual L, Mathieu Y, Golzio C, Rio M, Malan V, Boddaert N, Soufflet C, Picard C, Durandy A, Dobbie A, Heron D, Isidor B, Motte J, Newburry-Ecob R, Pasquier L, Tardieu M, Viot G, Jaubert F, Munnich A, Colleaux L, Vekemans M, Etchevers H, Lyonnet S, Amiel J. Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Hum Mutat. 2009 Apr;30(4):669-76. doi: 10.1002/humu.20935. (http://www.ncbi.nlm.nih.gov/pubmed/19235238?dopt=Abstract)
  • Giurgea I, Missirian C, Cacciagli P, Whalen S, Fredriksen T, Gaillon T, Rankin J, Mathieu-Dramard M, Morin G, Martin-Coignard D, Dubourg C, Chabrol B, Arfi J, Giuliano F, Claude Lambert J, Philip N, Sarda P, Villard L, Goossens M, Moncla A. TCF4 deletions in Pitt-Hopkins Syndrome. Hum Mutat. 2008 Nov;29(11):E242-51. doi: 10.1002/humu.20859. (http://www.ncbi.nlm.nih.gov/pubmed/18781613?dopt=Abstract)
  • Zweier C, Peippo MM, Hoyer J, Sousa S, Bottani A, Clayton-Smith J, Reardon W, Saraiva J, Cabral A, Gohring I, Devriendt K, de Ravel T, Bijlsma EK, Hennekam RC, Orrico A, Cohen M, Dreweke A, Reis A, Nurnberg P, Rauch A. Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet. 2007 May;80(5):994-1001. Epub 2007 Mar 23. (http://www.ncbi.nlm.nih.gov/pubmed/17436255?dopt=Abstract)
  • Zweier C, Sticht H, Bijlsma EK, Clayton-Smith J, Boonen SE, Fryer A, Greally MT, Hoffmann L, den Hollander NS, Jongmans M, Kant SG, King MD, Lynch SA, McKee S, Midro AT, Park SM, Ricotti V, Tarantino E, Wessels M, Peippo M, Rauch A. Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients. J Med Genet. 2008 Nov;45(11):738-44. doi: 10.1136/jmg.2008.060129. Epub 2008 Aug 26. (http://www.ncbi.nlm.nih.gov/pubmed/18728071?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: May 2011
Published: December 22, 2014