Pitt Hopkins Syndrome

What is Pitt Hopkins Syndrome?

Pitt Hopkins is a rare genetic disorder that results from a mutation of TCF4 gene or a deletion in the region of 18th chromosome where TCF4 gene is located. TCF4 is a transcription factor. Mutations or deletions in this region disrupt body’s ability to carry out the normal nervous system development and function resulting in the developmental delay and intellectual disability. There are approximately 250 known cases with PTHS. It is inherited through an autosomal dominant pattern. One copy of the altered gene causes PTHS. Most cases result from new mutations with no history of disorder in the family. (6)

Pitt Hopkins Syndrome 2

Signs and symptoms

The main symptoms of the condition are severe. They may include:

Intellectual disability

Intellectual disability of the individuals with Pitt Hopkins syndrome have moderate to severe. Motor skills are generally quite delayed which includes walking. Children often have a wide-based and an unsteady gait.  Expressive language is limited or totally absent. For some people receptive language skills are relatively intact.  Multimodal strategies including symbol exchange, gesture, and voice-output devices enable communication for some affected persons with Pitt Hopkins syndrome.

Breathing Issues

Hyperventilation like rapid breathing that is followed by periods of apnea like slowed breathing or breath holding can be triggered by emotions or fatigue.  Such breathing anomalies disappear in sleep.  Patients may appear blue in lips or skin, lose consciousness, and develop widened and rounded fingers and toes. This is due to chronic, decreased levels of oxygen.


Recurring seizures affect about half of the people diagnosed with Pitt Hopkins syndrome.

Eyes and Vision

Vision problems are in common with Pitt Hopkins syndrome. These may include severe near-sightedness (myopia)and crossed eyes (strabismus).

Facial features

  • A wide mouth
  • Strabismus
  • Prominent cupid’s bow
  • Myopia
  • Ears with thick and over folded helix
  • Tented upper lip
  • Everted lower lip
  • Marked nasal root
  • Deep set eyes
  • Broad and beaked nasal bridge
  • Widely spaced teeth
  • Deep-set eyes
  • Wide and shallow palate

Individuals with this syndrome are often short compared to other members of their family. They may also have a smaller head size. Seizures may be present. Brain scans often show some specific abnormalities. There are minor differences in the shape of fingers and slim feet are also found. Constipation may also be one of the problems. Speech is very limited in Pitt Hopkins syndrome. People with Pitt Hopkins syndrome have a tendency to smile frequently and some unsteadiness on walking. Constipation is a prominent feature of PTHS.   (7), (8), (10)

Risk factors

A parent with a mosaicism would pass the change in the gene to all cells of a child. This child may have the change in all body cells but not in a mosaic form. A brother or sister who is healthy and did not inherit the changed gene has no increased risk for getting a child with Pitt-Hopkins.

In 2009 a German group described two families with each two children in family with Pitt-Hopkins. At the beginning these were characterized as having Pitt-Hopkins but after a while they realized that they in fact only resembled Pitt-Hopkins syndrome. In these families they found that in each family the affected child had two changes in one of two genes i.e CNTNAP2 and NRXN1. In these families the gene was inherited in an autosomal recessive way. (9)

Causes of Pitt Hopkins

Genetic Basis

Pitt Hopkins syndrome is caused by mutation within or a complete deletion of TCF4 gene. Genes are instructions that tell the body how to grow and develop. Genes are located on chromosomes. Deletions and changes which are called mutations, the TCF4 cause the gene to stop working properly. At this stage the body miss an important instruction. This result to the medical and developmental problems associated with Pitt Hopkins syndrome. Changes in CNTNAP2 and NRXN1 genes are responsible for medical and developmental features similar to those found in Pitt-Hopkins syndrome.

18q- and PTHS

TCF4 gene is located on the long arm of chromosome 18. Some individuals who have distal 18q- miss TCF4gene. Such individuals often have similar findings to patients with PTHS. But these individuals referred to having 18q-. The reason may be due to additional features of PTHS the individuals may also have features commonly associated with distal 18q-, such as narrow ear canals and growth hormone deficiency. (1),(4),(6)

How to diagnose Pitt Hopkins Syndrome?

MRI findings

Many people with Pitt Hopkins syndrome have changes in brain that can only be detected with an MRI. The most common change found is a small corpus callosum. This corpus callosum is a bundle of nerves that connects the left and right side of the brain. This can be associated with some of the neurological problems.

Changes in the caudate nucleus have also been observed. The caudate nucleus is a part of brain involved with learning and memory. The effects of these changes are not well-understood.

Eyes and vision

The vision problems are common in people with Pitt Hopkins syndrome. Eyes may be crossed called strabismus and near-sightedness called myopia has also been reported. As vision problems are possible with PTHS people should have regular eye exams.


People with Pitt Hopkins syndrome may have a curvature of spine called scoliosis. Foot abnormalities are fairly common in this syndrome. The most common foot problem is flat feet that is also called pes planus. Many people with PTHS have small and slender feet.

These individuals may consult an orthopedic specialist. Braces and inserts, surgery, and therapy may help in addressing orthopedic concerns.


Males with Pitt Hopkins syndrome may have some changes in genital region. The testicles may not be fully descended. Some of the cases may require surgical correction.


The most common gastrointestinal problem with Pitt Hopkins syndrome is chronic constipation. This may happen during infancy, childhood, or adults. Medication may help such problem. Another common problem with this syndrome is reflux. Reflux occurs when stomach contents flow upwards. This leads to pain, irritability, and vomiting. Medication may be helpful for people with reflux. Severe cases require surgery.

Hirschsprung disease has been reported in an individual with PTHS. This condition involves a change in nerves of large intestines. Pyloric stenosis is also been found with Pitt Hopkins syndrome. Pyloric stenosis is a closure or narrowing of place where stomach contents enter intestines. For these problems, a referral to a gastroenterologist is appropriate.


Generally people with PTHS are shorter than other children and adults of same age. In addition to short stature, many individuals with PTHS have microcephaly or a head size that falls below the 3rd percentile. (2), (3), (5)

Treatment and Therapies

Treatment for Pitt Hopkins Syndrome is symptomatic and currently there is no known cure for it.

Affected individuals often benefit from glasses and assistive communication devices.  Symptoms like seizures, constipation and hyper breathing are managed with medication. Hippo therapy,  Physical therapy, slanders and braces are some of the modalities used to help individuals and build strength in order to lessen physical limitations. Sensory integration, speech, and behavioural therapies can help increase the quality of life for an affected individual. (8)


Most treatment strategies for the genetic disorders do not alter the underlying genetic mutation. A few disorders have been treated with gene therapy. This experimental technique involves changing a person’s genes to prevent or treat the disease. Gene therapy along with many other treatment and management approaches for genetic conditions are under study in clinical trials. (10)


Pitt Hopkins Syndrome 3

Pitt Hopkins Syndrome 4

Pitt Hopkins Syndrome


  1. Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, Plouin P, Carter NP, Lyonnet S, Munnich A, Colleaux L (2007). 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 80: 988-993.
  2. Andrieux J, Lepretre F, Cuisset JM, Goldenberg A, Delobel B, Manouvrier-Hanu S, Holder-Espinasse M (2008). Deletion 18q21.2q21.32 involving TCF4 in a boy diagnosed by CGH-array. Eur J Med Genet 51: 172-7.
  3. Ardinger H, Welsh H, Saunders C (Updated August 30, 2012). Pitt-Hopkins Syndrome. In: Genereviews at eneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013.
  4. 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 (2007). Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum Molec Genet 16(12): 1488-94.
  5. Giurgia 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, Lambert JC, Philip N, Sarda P, Villard L, Goossens M, Moncla A (2008). TCF4 Deletions in Pitt-Hopkins Syndrome. Hum Mutat 29(11): E242-51.
  6. Pitt D, Hopkins I (1978) A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust Paed J 14(3):182-184
  7. Rosenfeld JA, Leppig K, Ballif BC, Thiese H, Erdie-Lalena C, Bawle E, Sastry S, Spence JE, Bandholz A, Surti U, Zonana J, Keller K, Meschino W, Bejjani BA, Torchia BS, Shaffer LG (2009). Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genet Med 11(11): 797-805.
  8. Zweier C, Peippo MM, Hoyer J, Sousa S, Bottani A, Clayton-Smith J, Reardon W, Saraiva J, Cabral A, Göhring I, Devriendt K, de Ravel T, Bijlsma EK, Hennekam RCM, Orrico A, Cohen M, Dreweke A, Reis A, Nürnberg P, Rauch A (2007). Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet 80: 994-1001.
  9. 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 (2008). Future delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients. J Med Genet 45: 738-744.
  10. Zweier C, de Jong EK, Zweier M, Orrico A, Ousager LB, Collins AL, Bijlsma EK, Oortveld MAW, Ekici AB, Reis A, Schenck A, Rauch A (2009). CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 85: 655-666.

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