NORD gratefully acknowledges David Sweetser, MD PhD, Chief of Medical Genetics and Metabolism, Co-Director of the MGH Pitt Hopkins Clinic, Massachusetts General Hospital, for assistance in the preparation of this report.
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 affected individual to another. Pitt-Hopkins syndrome is caused by a change (mutation) in the TCF4 gene. This mutation occurs spontaneously and in almost all instances, does not run in a family. The disorder was first described in the medical literature in 1978 and the causative gene was discovered in 2008.
With the publication of an increasing number of case series we are developing a better picture of associated symptoms and prognosis of individuals with Pitt-Hopkins syndrome. However, much about the disorder is not fully understood. It is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
Infants with Pitt-Hopkins syndrome may have diminished muscle tone (hypotonia) and 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. They may be described as very quiet and sleep excessively. Some infants may exhibit an abnormally small head circumference (postnatal microcephaly).
Affected infants and children experience delays in reaching developmental milestones, including sitting up or holding one’s head up. They are usually significantly delays in learning to walk. Some children will only be able to walk with assistance while others may be unable to walk. Most children benefit from bracing to stabilize loose ankles. Children who can walk may have an unsteady manner of walking with a wide gait. They may exhibit a lack of coordination (ataxia) and be clumsy. Speech is significantly delayed. Some children develop the ability to speak a few words, but many children are unable to speak. 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. These children can benefit from assistive communication devices including picture boards and tablet based speaking devices. Many are able to learn and communication to a degree with sign language.
Most affected children have moderate to severe intellectual disability. However, speech and motor abnormalities make it difficult to determine a child’s true mental capacity. Advances in technology and new therapies have enabled affected children to achieve more than originally believed and some physicians and parents believe that there is a broader range of intellectual capability than is generally reported in the medical literature.
Infants and children typically have distinctive facial features. These features include an abnormally wide mouth with a full lower lip; widely-spaced teeth; flared nostrils; a broad bridge of the nose; a sharp, downturned nasal tip; mildly cup-shaped ears; and deep-set eyes that slant slightly upward with a prominent supraorbital ridge. They may have a protruding upper lip that is curved twice (Cupid’s bow), full cheeks and the lower part of the face and chin may be prominent. These distinctive facial features may become more pronounced or noticeable with age.
Children with Pitt-Hopkins syndrome can have irregular or abnormal breathing patterns. They may experience recurrent episodes where they breathe very fast (hyperventilation), often followed by episodes where they struggle to breath 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. Breathing problems usually do not occur during sleep. The age of onset of breathing abnormalities can vary and has ranged from anywhere from 7 months to 7 years.
Affected children are described as sociable and having a happy disposition, frequently laughing and smiling. Laughter may occur spontaneously or at inappropriate times. However, some children may be quiet or withdrawn into their own world (self-absorption) and have difficulties engaging socially. 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. Children with Pitt-Hopkins syndrome also exhibit stereotypic hand movements, which include hand clapping, hand flapping, flicking hands, hand washing, fingers crossing, and frequent hand-to-mouth movements. Head shaking, head banging, body rocking, teeth grinding (bruxism) and hair pulling may also be seen. Children may repeatedly and repetitively play with a toy, and may show a fascination with one specific part of a toy.
Seizures 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 teen-age years. Most children experience constipation, which can be severe. Gastroesophageal reflux has been reported in less than half of affected individuals. Most individuals have a high pain threshold.
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 occurred in a small number of individuals. Approximately one third of affected males experience failure of one or both testicles to 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 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 baes of the nail (clubbing). They often have overriding toes. Hands and feet may be cold or bluish in appearance due to cyanosis.
Pitt-Hopkins syndrome is caused by an unexpected change (mutation) in the TCF4 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular 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.
In cases where a mutation in TCF4 is disease causing, Pitt-Hopkins syndrome almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation 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. The disorder is usually not inherited from or “carried” by a healthy parent.
If the mutation were to be passed on from an affected individual to a child, in most instance this would occur in an autosomal dominant manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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 mutation. The other cells in the parent’s body do not have the mutation, so these parents are unaffected but can pass an altered gene to their children. Because of this possibility, we estimate 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 mutation in their blood.
Investigators have determined that 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 the 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.
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. Approximately 500 affected individuals have been identified worldwide. Researchers believe that affected individuals often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency the disorder in the general population. Intellectual disability (due to all causes) affects approximately 1%-3% of the general population.
A 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, which can generally be confirmed by molecular testing demonstrating a specific change (mutation) or deletion involving the TCF4 gene. This gene is often included on gene panels that can be ordered for individuals with features of Pitt-Hopkins/Rett/Angelman syndromes. There are individuals with clinical features that can’t be distinguished from Pitt-Hopkins syndrome for which no mutation in TCF4 can be found, and some individuals with variants in TCF4 with a phenotype differing from Pitt-Hopkins syndrome. Diagnostic criteria have been published based on published cases, but are being redefined as more molecularly confirmed cases have been identified.
Clinical Evaluations and Workup
If the diagnosis is suspected by exam and history, molecular testing can be ordered. If the diagnosis is confirmed, investigations for other congenital malformations such a heart or kidney defects are only needed if there is a specific clinical concern, as there is not an increased incidence for these with Pitt-Hopkins syndrome.
If seizure activity is seen or suspected – body shaking or staring spells, physicians 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 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 particular organs and bodily tissues, including the brain. Physicians 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.
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 your 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 may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is of benefit 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 these 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. If there is a significant problem with hyperventilation and/or apnea, advice from a pulmonologist should be sought as in some instances medications such as antiepileptic medications or acetazolamide have been helpful. Seizures that may occur are generally well controlled by anticonvulsants that can be individualized by a neurologist. Most individuals with Pitt-Hopkins will benefit from glasses and some may need surgery for crossed eyes that fail to self-correct. Regular ophthalmology exams are recommended.
As of April 2018, Pitt-Hopkins syndrome clinics have been established at Massachusetts General Hospital (https://www.massgeneral.org/children/services/treatmentprograms.aspx?id=1849), University of Texas Southwestern’s Children’s Health (https://www.childrens.com/specialties-services/specialty-centers-and-programs/autism-and-developmental-disabilities/conditions-and-treatments/pitt-hopkins-syndrome), and UCSF Benioff Children’s Hospital San Francisco (https://www.ucsf.edu/news/2015/09/131486/ucsf-pediatric-clinic-focused-rare-pitt-hopkins-syndrome-third-its-kind-world). These centers are devoted to the diagnosis and comprehensive treatment of this disorder and to further research to better understand this disorder.
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:
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Some current clinical trials also are posted on the following page on the NORD website:
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Genetics and Rare Disease (GARD) Information Center. Pitt-Hopkins Syndrome. February 2015. Available at: https://ghr.nlm.nih.gov/condition/pitt-hopkins-syndrome Accessed February 23, 2018.
Pediatric Brain Foundation. Pitt-Hopkins Syndrome. 2015. Available at: http://www.pediatricbrainfoundation.org/educate/disorder/pitt-hopkins-syndrome-pths Accessed February 23, 2018.
Sweetser DA, El Sharkawi I, Yonker L, et al. Pitt-Hopkins Syndrome. 2012 Aug 30 [Updated 2018 Apr 12]. 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 April 24, 2018.
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