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

People with Pitt-Hopkins syndrome have moderate to severe intellectual disability. Most affected individuals have delayed development of mental and motor skills (psychomotor delay). They are delayed in learning to walk and developing fine motor skills such as picking up small items with their fingers. People with Pitt-Hopkins syndrome typically do not develop speech; some may learn to say a few words. Many affected individuals exhibit features of autistic spectrum disorders, which are characterized by impaired communication and socialization skills.

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 in mid-childhood, but 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, an unusually small head (microcephaly), nearsightedness (myopia), eyes that do not look in the same direction (strabismus), short stature, and minor brain abnormalities. Affected individuals may also have small hands and feet, a single crease across the palms of the hands, flat feet (pes planus), or unusually fleshy pads at the tips of the fingers and toes. Males with Pitt-Hopkins syndrome may have undescended testes (cryptorchidism).

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.

Normal Function

The TCF4 gene provides instructions for making a protein that attaches (binds) to specific regions of DNA and helps control the activity of many other genes. On the basis of this action, the TCF4 protein is known as a transcription factor. The TCF4 protein is part of a group of proteins known as E-proteins. E-proteins each bind with another identical or similar protein and then bind to a specific sequence of DNA known as an E-box. E-proteins are involved in many aspects of development.

The TCF4 protein is found in the brain, muscles, lungs, and heart. This protein also appears to be active (expressed) in various tissues before birth. 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).

Health Conditions Related to Genetic Changes

Pitt-Hopkins syndrome

At least 50 mutations in the TCF4 gene have been found to cause Pitt-Hopkins syndrome, a condition characterized by severe intellectual disability and breathing problems. Some mutations delete a few building blocks of DNA (nucleotides) within the TCF4 gene, while other mutations delete the TCF4 gene as well as a number of genes that surround it. Still other TCF4 gene mutations replace single nucleotides. The type of the mutation does not appear to affect the severity of the condition.

TCF4 gene mutations disrupt the protein's ability to bind to DNA and control the activity of certain genes. These gene mutations typically do not affect the TCF4 protein's ability to bind to other proteins. The TCF4 protein's inability to bind to DNA and control the activity of certain genes, particularly those genes involved in nervous system development and function, contributes to the signs and symptoms of Pitt-Hopkins syndrome. 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.

Distal 18q deletion syndrome

The TCF4 gene is involved in some cases of a condition called distal 18q deletion syndrome, which occurs when a piece of the long (q) arm of chromosome 18 is missing. The term "distal" means that the missing piece occurs near one end of the chromosome. Distal 18q deletion syndrome can lead to a wide variety of signs and symptoms among affected individuals, depending on which genes in this part of chromosome 18 are affected. People with this disorder whose deletions include the TCF4 gene usually have signs and symptoms of Pitt-Hopkins syndrome (described above) in addition to other features of distal 18q deletion syndrome that are likely associated with the loss of nearby genes.

Fuchs endothelial dystrophy

MedlinePlus Genetics provides information about Fuchs endothelial dystrophy

Other Names for This Gene

• bHLHb19
• class B basic helix-loop-helix protein 19
• E2-2
• immunoglobulin transcription factor 2
• ITF-2
• ITF2
• ITF2_HUMAN
• SEF-2
• SEF2
• TCF-4

Genomic Location

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.

Pitt-Hopkins syndrome (PTHS) can have a variety of signs and symptoms. Specific symptoms present and their severity can vary from person to person. Early symptoms, which often become apparent in the first year of life, may include very low muscle tone (hypotonia) and significant developmental delays. Some infants have a small head size (microcephaly). Children may learn to walk months or years later than expected, and some children never acquire the skills to walk independently. Speech is significantly delayed, and while some children learn to say a few words, most do not speak. However, some are able to understand and follow simple directions. Intellectual disability generally ranges from moderate to severe.

Additional signs and symptoms of PTHS may include:

• Behavioral differences: Symptoms of autism spectrum disorder may be present. Other behavioral characteristics that have been reported include unusual behavior during feeding, aggressive outbursts, anxiety, hand biting and head banging, and other stereotypic hand or head movements. However, many children with PTHS are described as having happy dispositions.
• Distinctive facial features: These may become more obvious with age and may include deeply-set eyes, a prominent nose, short philtrum, wide mouth, full lower lip, widely-spaced teeth, and/or a prominent chin.
• Breathing problems: These may include episodes of rapid breathing (episodic hyperventilation) followed by episodes of struggling to breath or not breathing. Episodes of breathing problems may be triggered by anxiety, excitement, or tiredness. Failure to breathe may cause a bluish discoloration of the skin (cyanosis) or fainting.
• Seizures: These occur in almost half of people with PTHS, and the type and severity varies. Seizures may begin any time during childhood or adolescence.
• Sleep disturbances: These may include problems falling asleep or staying asleep, and/or night terrors.
• Eye or vision problems: Nearsightedness (myopia) can be severe and may become apparent before 2 years of age. Other eye abnormalities may include misalignment (strabismus) and astigmatism.
• Gastrointestinal problems: These may include early feeding issues (which often resolve), constipation (which can be severe), and reflux.
• Skeletal features: Those that have been reported in people with PTHS include scoliosis, flat feet, clubfoot, small hands and feet, broad fingertips or tapered fingers, bent or curved finger (clinodactyly), and overlapping toes.

• Early intervention services for infants and young children, which may include occupational, physical, speech and feeding therapies.
• An individualized education plan (IEP) for preschool and school-aged children.
• Behavioral therapies - children may benefit from treatments for autism spectrum disorder (such as applied behavioral analysis, or ABA) or medications.
• Consideration of medication for significant breathing problems. Some individuals with PTHS have reported improvement of breathing problems with antiepileptic drugs or acetazolamide.
• Routine treatment of seizures, nearsightedness, constipation, and orthopedic problems.
• The use of durable medical equipment (such as wheelchairs, walkers, and adaptive strollers) as needed.

Pitt-Hopkins syndrome is thought to be a very rare condition. Approximately 500 affected individuals have been reported worldwide.