Pitt-Hopkins syndrome is a genetic condition that is present from birth (congenital). It is characterised by developmental delay, intellectual disability, certain facial features as well as abnormal and irregular breathing such as rapid breathing (hyperventilation/hyperbreathing) and pauses in breathing (apnea).^1-3 Other features include short-sightedness (myopia), gastrointestinal issues such as constipation, and repetitive hand movements and mannerisms, and seizures.

Pitt-Hopkins syndrome is caused by genetic changes (variants) in the TCF4 gene.^4,5 These genetic variants typically occur randomly (de novo) before birth, and are rarely inherited.⁶ Both males and females can have a diagnosis of Pitt-Hopkins syndrome.² Management of the condition involves a multidisciplinary medical team and care is often life-long.

There are no known synonyms.

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:2896 Pitt-Hopkins syndrome

ICD-11: LD2F.1Y Other specified syndromes with multiple structural anomalies, not of environmental origin

Common features of Pitt-Hopkins syndrome include, but are not limited to, the following:^{1-3, 6-8}

• developmental delays
• intellectual disability with limited or no speech
• low muscle tone (hypotonia) in infants
• characteristic facial features, such as narrow forehead, thin lateral eyebrows, broad nasal bridge (top portion of the nose wider than usual), flared nasal alae (nostrils), full cheeks, wide mouth/full lips/cupid bow upper lip (shaped like the letter ‘M’), thickened or overfolded helices of the ears; these features may become more prominent with age
• rapid breathing (hyperventilation)
• pauses in breathing or breath-holding (apnea)
• constipation
• issues with vision, including early-onset short-sightedness (myopia)
• seizures
• repetitive hand gestures and mannerisms
• behavioural attributes, such as anxiety, agitation, a ‘smiling’ appearance, inappropriate laughing as well as other features on the autism spectrum

Further information about the clinical description of Pitt-Hopkins syndrome can be found at GeneReviews®: Pitt-Hopkins syndrome (Clinical Characteristics section).

Please speak to your medical team to learn more about the features and health implications associated with Pitt-Hopkins syndrome.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

Pitt-Hopkins syndrome is a genetic condition. It is caused by disease-causing genetic changes (variants) in the TCF4 gene on Chromosome 18.^4,5 These genetic changes include single base changes (sequence variants/ a single letter changes in the genetic code), deletions, insertions, duplications as well as translocations that span the TCF4 locus.^4-7 For more information on different types of genetic variants, please refer to Centre for Genetics Education: Types of genetic variation.

All individuals has two copies (alleles) of the TCF4 gene – one on each chromosome that is inherited from each parent. Pitt-Hopkins syndrome is an autosomal dominant condition, which means that having a genetic variant in just one of the TCF4 gene copies can result in Pitt-Hopkins syndrome.

For most individuals with Pitt-Hopkins syndrome, their genetic variant in the TCF4 gene occurs randomly (de novo) prior to birth and is not passed down (inherited) from their parents.⁶ In rare cases, the autosomal dominant genetic variant was inherited from a parent who has the genetic change in some but not all of their cells (this is called genetic mosaicism); the parent often has typical learning abilities and health.^2,3 More information on genetic mosaicism can be found at Centre for Genetics Education: Mosaicism.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

Diagnosis of Pitt-Hopkins syndrome may be considered based on clinical features, and confirmed by genetic testing.

Information about internationally recommended clinical diagnostic criteria for Pitt Hopkins syndrome can be found at Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.

Genetic testing for Pitt-Hopkins syndrome may include chromosomal microarray analysis (CMA), exome or genome sequencing, gene-targeted testing or karyotyping, to identify changes in the TCF4 gene.^1,2

General information about these genetic tests can be found at:

• Pathology Tests Explained: Genome-wide chromosome microarray testing
• Pathology Tests Explained: Whole Genome or Whole Exome Testing for Childhood Syndromes

A differential diagnosis can rule out other conditions that have similar symptoms, such as Angelman syndrome, Rett syndrome and Mowat-Wilson syndrome.³

Please speak to your medical team to learn more about the available diagnostic pathways for Pitt-Hopkins syndrome.

There is currently no curative treatment for Pitt-Hopkins syndrome. Treatment is targeted at managing symptoms (symptomatic management) and improve quality of life. This involves a multidisciplinary care team, and care is often life-long. Management strategies may include speech and language therapy, physiotherapy, occupational therapy, use of orthotics and assistive equipment as well as augmentative and alternative communication (AAC) tools and management of constipation.¹

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities.

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

Healthcare professionals involved in the treatment of Pitt-Hopkins syndrome may include general practitioners (GP), paediatricians, geneticists, neurologists, gastroenterologists, pulmonologists, orthopedic specialists, ophthalmologists, audiologists, speech therapists, occupational therapists, physiotherapists, psychologists and psychiatrists.¹ The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.

We are not aware of any clinical care guidelines for Pitt-Hopkins syndrome in Australia. If you know of any relevant care guidelines, please let us know via the Contribute page.

The following guidance is available from international experts outside Australia; however, there may be information that is not relevant or applicable to the Australian context, and may not be up to date:

• Diagnosis and management in Pitt‐Hopkins syndrome: First international consensus statement – developed by a consensus group consisted of 32 participants (which included clinicians, molecular geneticists, clinical and research scientists, and patient group representatives) from 24 institutions from 7 countries; published in 2019

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

It may be important to consider the following when managing individuals living with Pitt-Hopkins syndrome at emergency departments/services:

• individuals with Pitt-Hopkins syndrome may have severe intellectual disability, with limited or absent speech
• they may need 24/7 attendant/carer support in Emergency and Hospital
• they may not be able to communicate with spoken words and may use alternative communication methods such as key word sign, sign language or Alternative and Augmentative Communication tools and devices
• they may have seizures

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in any clinical trials with your medical team to determine suitability and eligibility.

Please note that RVA does not necessarily monitor or endorse each group/organisation’s operational governance and activities.

We are not aware of any Pitt-Hopkins syndrome support organisation in Australia. If you know of any relevant Australian organisation, please let us know via the Contribute page.

International Organisation:

Pitt Hopkins Research Foundation (United States of America)
Website: https://pitthopkins.org/

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

Pitt-Hopkins syndrome varies between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease, including families and carers, often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many people find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information on Pitt-Hopkins syndrome can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Pitt hopkins syndrome
• National Organization for Rare Disorders (NORD): Pitt-Hopkins syndrome

• GeneReviews^®: Pitt-Hopkins Syndrome
• Online Mendelian Inheritance in Man, OMIM^®: #610954 Pitt-Hopkins syndrome, PTHS
• Orphanet: Pitt-Hopkins syndrome

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.