Pitt-Hopkins Syndrome

Disease Overview

Summary

Pitt-Hopkins syndrome (PTHS) is a rare, genetic, neurological disorder. Affected children have distinctive facial features and experience intellectual disability, delays in reaching developmental milestones, impaired ability to speak, and can have recurrent seizures and breathing pattern abnormalities. Additional symptoms that can occur include poor coordination (ataxia), repetitive nonfunctional hand movements, constipation, sleep disturbances and severe nearsightedness (myopia). Behavioral abnormalities are common, although children are often described as social and having happy dispositions. Some affected children meet the criteria for an autism spectrum disorder. The specific signs and symptoms of the disorder and their severity can vary from one child to another. Pitt-Hopkins syndrome is caused by a change (variant) in the TCF4 gene. Variants occur spontaneously in almost all affected people and are not inherited. The disorder was first described in the medical literature in 1978, and the causative gene was discovered in 2008.

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Synonyms

• PTHS

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Signs & Symptoms

As more case series are published, our understanding of the symptoms and prognosis of Pitt-Hopkins syndrome continues to improve. Still, much about the condition remains unclear. Not all individuals will show every symptom listed below. Families should consult their child’s doctor and care team to discuss their unique case, potential symptoms, and overall outlook.

Common signs and symptoms may include:

• Decreased muscle tone (hypotonia) in infants who may appear abnormally “floppy”
  • Hypotonia can affect feeding and impact motor skills such as walking
• Feeding difficulties may occur in infancy but tend to resolve once the child ages
• Abnormally small head circumference (postnatal microcephaly)
• Delays in reaching developmental milestones including:
  • Delays on sitting up or holding head up
  • Delays in learning to walk with some children being able to walk with assistance while others may be unable to walk
  • Most children benefit from bracing to stabilize loose ankles
  • Lack of coordination (ataxia) and clumsiness
  • Children who can walk may have an unsteady manner of walking with a wide gait
  • Delayed or absent speech
  • Most children have better receptive language skills, which means that they can understand more information spoken to them than they are able to speak themselves. They can benefit from assistive communication devices including picture boards and tablet based speaking devices and may communicate with sign language.
• Severe intellectual disability (in most children) that can be not very well evaluated due to speech and motor abnormalities

Advances in technology and new therapies have enabled affected children to achieve more than originally thought and some doctors and parents think there is a broader range of intellectual capabilities than is generally reported in the medical literature.

Other features may include:

• Distinctive facial features (evident in infants and children that may become more pronounced or noticeable with age) These features include:
• Abnormally wide mouth with a full lower lip
• Shallow and broad palate with widely spaced teeth and protruding jaw
• Flared nostrils
• Broad bridge of the nose; a sharp, downturned nasal tip
• Mildly cup-shaped ears
• Deep-set eyes that slant slightly upward with a prominent supraorbital ridge
• Protruding upper lip that is curved twice (Cupid’s bow)
• Full cheeks
• Prominent chin
• Irregular or abnormal breathing patterns that may start from 7 months to 7 years and may include:
• Recurrent episodes where they breathe very fast (hyperventilation), often followed by episodes where they struggle to breathe or momentarily stop breathing (apnea crises)
• Apnea can cause cyanosis, a condition in which there is abnormal bluish discoloration to the skin due to lack of oxygen.
• Breathing irregularities may be triggered by stress, strong emotions, or fatigue.
• Behavioral issues that can be very varied:
  • Quietness, social withdrawal and difficulty engaging with others; often marked by self-absorption
  • Happy and sociable disposition, frequently laughing and smiling in many children
  • Episodes of aggression or shouting or agitation, often in response to unexpected changes in routine occur as well
  • Additional behavioral issues are common and can include hyperactivity, anxiety, self-injury and shyness
  • Stereotypic hand movements which include hand clapping, hand flapping, flicking hands, hand washing, finger crossing and frequent hand-to-mouth movements
  • Head shaking, head banging, body rocking, teeth grinding (bruxism) and hair pulling
  • Repetitive behaviors where children may repeatedly and repetitively play with a toy, and may show a fascination with one specific part of a toy
• Seizures, which can occur in just under half of individuals and usually begin in childhood, but sometimes are present from birth or develop as late as the teenage years
• Constipation (in most people) which can be severe
• Gastroesophageal reflux, reported in less than half of affected individuals
• High pain threshold (in most people)

Additional symptoms can include excessive drooling (especially when younger), severe nearsightedness (myopia), crossed eyes (strabismus) and abnormal curving of the lens of the eye (astigmatism). Abnormal curving of the spine (scoliosis) has been reported in a small number of individuals. Approximately one third of affected males have one or both testicles that did not descend into the scrotum (cryptorchidism).

Some minor abnormalities of the hands may be seen including broad fingertips, tapered fingers, curved pinkies (clinodactyly), a single crease across the palm and prominent pads on the fingertips and toes (persistent fetal pads). There is often an extra crease or absent crease on the thumb and rare individuals are unable to bend the thumb due to an absent tendon. They often have redness and swelling of the skin at the base of their nails and can have blunting of the normal angle at the base of the nail (clubbing). They often have overriding toes. Hands and feet may be cold or bluish in appearance due to cyanosis.

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Causes

Pitt-Hopkins syndrome (PTHS) is usually caused by a disease-causing change, known as a pathogenic variant, in a gene called TCF4. In some people, it results from a missing segment (microdeletion) of chromosome 18 in the region known as 18q21.2, which includes the TCF4 gene. Less commonly, PTHS can be due to a structural change in the chromosomes, called a balanced rearrangement, that disrupts the TCF4 gene without deleting it.

Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene variant occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain. The TCF4 gene creates a protein that is a transcription factor. This protein has an important role in various developmental processes of the body. It is highly expressed early during human development and is found throughout the central nervous system.

The TCF4 gene is located on the long arm (q) of chromosome 18 (18q21.2). Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 18q21.2” refers to band 21.2 on the long arm of chromosome 18. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

In cases where a TCF4 gene variant is disease causing, Pitt-Hopkins syndrome almost always occurs as a new (sporadic or de novo) variant, which means that in nearly all cases the gene variant has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected and that the disorder is not inherited.

If the variant were to be passed on from an affected individual to a child, in most instances this would occur in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

There are several instances in which an unaffected parent has more than one child with Pitt-Hopkins syndrome. This extremely rare event occurred because of germline mosaicism. In germline mosaicism, one parent has some reproductive cells (germ cells) in the ovaries or testes that have the TCF4 gene variant. The other cells in the parent’s body do not have the variant, so these parents are unaffected but can pass the gene variant to their children. Because of this possibility, it is estimated that parents of a child with Pitt-Hopkins syndrome have about a 1-2% chance of having another affected child, even if the parents test negative for the variant in their blood.

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Affected populations

Pitt-Hopkins syndrome affects both males and females and can affect individuals of any ethnic or racial background. The exact incidence of the disorder is unknown. According to the Pitt Hopkins Research Foundation (PHRF) the global count of diagnosed individuals as of 2025 is about 1,564. This total includes all individuals with PTHS known to the PHRF and international support networks.  Researchers think that affected individuals often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Pitt-Hopkins syndrome. Comparisons may be useful for a differential diagnosis.

Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although people with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional common symptoms include seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene.

Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or later in childhood. MWS is characterized by intellectual disability, absent speech, distinctive facial features and seizures. Children with this disorder are more likely to have congenital anomalies including a gastrointestinal disease known as Hirschsprung disease (40-50% of individuals) in which a narrowing of a portion of the colon is present, eye (ophthalmologic) defects, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. MWS is caused by a variant in the ZEB2 gene that is usually not inherited.

Rett syndrome is a progressive neurodevelopmental disorder that almost exclusively affects females. Only in rare cases are males affected. Infants with Rett syndrome generally develop normally for about 7 to 18 months after birth. At this point, they lose previously acquired skills (developmental regression) such as purposeful hand movements and the ability to communicate. Additional abnormalities occur including impaired control of voluntary movements (ataxia) and the development of distinctive, uncontrolled hand movements such as hand clapping or rubbing. Some children also have slowed head growth (acquired microcephaly). Affected children often develop autistic-like behaviors, feeding and swallowing difficulties, growth delays and seizures. Like Pitt-Hopkins syndrome, these individuals can also develop spells of hyperventilation and apnea. Rett syndrome is usually caused by variants of the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. T

Some children with changes (variants) in the CNTNAP2 gene or the NRX1 gene have developed similar symptoms as children who have Pitt-Hopkins syndrome, including absent speech and global developmental delays. These disorders are known as CTNAP2-associated autosomal recessive intellectual disability disorder (or Pitt-Hopkins-Like syndrome 1), and NRX1-associated autosomal recessive intellectual disability disorder (or Pitt-Hopkins-Like syndrome 2). These disorders are extremely rare and affected children do not have the same distinctive facial features as seen in children with Pitt-Hopkins syndrome. They also have abnormal sleep-wake cycles.

Additional disorders in which children exhibit intellectual disability, seizures, constipation, breathing abnormalities, stereotypic movements, and distinctive facial features include MECP2 duplication syndrome, alpha thalassemia/intellectual disability syndrome, congenital central hypoventilation syndrome (CCHS), Joubert syndrome and Partington syndrome (ARX-related intellectual disability disorder). These disorders have characteristics features that can distinguish them from Pitt-Hopkins syndrome.

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Diagnosis

The diagnosis of Pitt-Hopkins syndrome depends upon a detailed patient history, a thorough clinical evaluation and identification of characteristic symptoms. There is overlap among symptoms associated with Pitt-Hopkins syndrome and other similar neurological disorders. The lack of major congenital malformations, which are structural or functional abnormalities that are present at birth, supports a diagnosis. The diagnosis is confirmed in someone with suggestive clinical features and one of the following on molecular genetic testing:

• A disease-causing variant (pathogenic or likely pathogenic) in the TCF4 gene (in about 70% of affected individuals)
• A microdeletion of chromosome 18q21.2 that includes TCF4 (in about 30% of affected individuals)

When the disease is caused by microdeletions of the 18q21.2 which include the TCF4 gene, standard genetic tests may miss it, so a more detailed test called chromosomal microarray (CMA) is needed to detect it.

Clinical Evaluations and Workup
If seizure activity is seen or suspected due to body shaking or staring spells, doctors may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and help to detect seizures.

An advanced imaging techniques called magnetic resonance imaging (MRI) of the brain may also be performed. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues, including the brain. Doctors use an MRI to obtain a detailed image of a major region of the brain called the cerebrum. A variety of nonspecific brain MRI findings have been seen in Pitt-Hopkins syndrome, though many studies are reported as normal.

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Standard Therapies

Treatment is directed toward the specific symptoms that are apparent in each individual and generally requires a team of specialists that can be coordinated by a medical geneticist or pediatrician. Members of this team may include a pediatric neurologist (a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children), a gastroenterologist (a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract), an ophthalmologist (a physician who specializes in the diagnosis and treatment of disorders of the eye), a pulmonologist (a physician who specializes in the diagnosis and treatment of disorders of the lungs and breathing issues), a speech pathologist, psychologist, and other healthcare professionals who can systematically and comprehensively plan an affected child’s treatment.

Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.

Following an initial diagnosis, it is recommended that a developmental assessment be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. Given the likelihood of severe speech impairment, strong consideration should be given to early training with alternative and augmentative communication devices. Children may benefit from treatments used in the treatment of autism spectrum disorder such as applied behavioral analysis (ABA) therapy targeted to the strengths and weaknesses of each child. A developmental pediatrician can help with management of behavioral issues and medication considerations, while more serious aggressive behaviors may be helped by a pediatric psychiatrist. In individuals who have limited communication, potential medical issues such as severe constipation that might adversely impact behavior should be considered.

Constipation is very common with Pitt-Hopkins and usually standard measures such as high fiber diets or laxatives are sufficient for treatment. If there is a significant problem with hyperventilation and/or apnea, advice from a pulmonologist should be sought medications such as antiepileptic medications or acetazolamide have been helpful in some children. Seizures are generally well controlled by anticonvulsants that can be individualized by a neurologist. Most individuals with Pitt-Hopkins need glasses and some may need surgery for crossed eyes that fail to self-correct. Regular ophthalmology exams are recommended.

There are several specialized clinics for Pitt-Hopkins syndrome in United States. The Pitt-Hopkins Research Foundation list the current clinics in the following link: https://pitthopkins.org/newly-diagnosed/clinics/

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Clinical Trials and Studies

The Pitt-Hopkins Research Foundation manages a family registry. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments and accelerate clinical trials into specific treatment options. For more information visit: https://pitthopkins.org/family-registry/.

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Ajina Khan AR, Baby B, Akhil SL, Sundaram S, Valaparambil KA. Pitt Hopkins syndrome – TCF4 gene deletion causing severe psychomotor delay, Human Gene 2024; 41: 201323. https://doi.org/10.1016/j.humgen.2024.201323

Goodspeed K, Newsom C, Morris MA, et al. Pitt-Hopkins syndrome: a review of current literature, clinical approach, and 23-patient case series. J Child Neurol. 2018;33:233-244. https://www.ncbi.nlm.nih.gov/pubmed/29318938

Bedeschi MF, Marangi G, Calvello MR, et al. Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4. Eur J Med Genet. 2018;60:565-571. https://www.ncbi.nlm.nih.gov/pubmed/28807867

de Winter CF, Baas M, Bijlsma EK, et al. Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system. Orphanet J Rare Dis. 2016;11:37. https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0422-2

Rannals MD, Page SC, Campbell MN, et al. Neurodevelopmental models of transcription factor 4 deficiency converge on a common ion channel as a potential therapeutic target for Pitt-Hopkins syndrome. Rare Dis. 2016;4:e1220468. https://www.ncbi.nlm.nih.gov/pubmed/28032012

Marangi G, Zollino M. Pitt-Hopkins syndrome and differential diagnosis: a molecular and clinical challenge. J Pediatr Genet. 2015;4:168-176. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918722/

Van Balkom ID, Vuijk PJ, Franssens M, Hoek HW, Hennekam RC. Development, cognition, and behaviour in Pitt-Hopkins syndrome. Dev Med Child Neurol. 2012;54:925-931. https://www.ncbi.nlm.nih.gov/pubmed/22712893

Peippo M, Ignatius J. Pitt-Hopkins syndrome. Mol Syndromol. 2012;2(3-5):171-180. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366706/

Whalen S, Heron D, Gaillon T, et al. Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum. Hum Mutat. 2012;33:64-72.

Marangi G, Ricciardi S, Orteschi D, et al. The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria. Am J Med Genet A. 2011;155A:1536-1545. https://www.ncbi.nlm.nih.gov/pubmed/21671391

INTERNET

Pediatric Brain Foundation. Pitt-Hopkins Syndrome. 2015. Available at: https://www.pediatricbrainfoundation.org/educate/disorder/pitt-hopkins-syndrome-pths Accessed Sept 9, 2025.

Sweetser DA, El Sharkawi I, Yonker L, et al. Pitt-Hopkins Syndrome. 2012 Aug 30 [Updated May 22, 2025]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK100240/ Accessed Sept 9, 2025.

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