Introduction
The goal of this page is to describe the major features of Pitt-Hopkins syndrome (PHS). This information may help you and your healthcare team make decisions about how to care for a person with PHS.
Background
Pitt-Hopkins syndrome was first described by two physicians in 1978. Until recently, the diagnosis of Pitt-Hopkins syndrome was based on a person’s medical history and a physical examination. Recently, new technology has allowed scientists to identify the genetic cause of Pitt-Hopkins syndrome. Now, the diagnosis of PHS is often based on the results of a blood test. It is estimated that PHS happens in about 1 in ever 34,000-41,000 births.
Genetic Basis
PHS is caused by a mutation within or a complete deletion of the TCF4 gene. Genes are simply the instructions that tell the body how to grow and develop. Genes are located on the chromosomes. For more information about genetics, please visit our Genetics FAQ’s page.
Deletions and changes (also called mutations) in the TCF4 cause the gene to stop working properly. The body is then missing an important instruction. This leads to the medical and developmental problems associated with PHS.
Unlike the other conditions discussed on this website, PHS is not diagnosed with a chromosome analysis. More specialized testing, such as microarray analysis or sequencing, is required.
18q- and PHS
The TCF4 gene is located on the long arm of chromosome 18. Some individuals that have 18q- are missing the TCF4 gene. These individuals may have similar findings to patients with PHS; research is currently ongoing to determine whether/how they may differ from individuals with changes involving only the TCF4 gene. We usually still refer to individuals with large deletions including TCF4 as having 18q-. This is because, in addition to the features of PHS, they may also have features commonly associated with 18q-, such as growth hormone deficiency and narrow ear canals.
Families with 18q- may wonder whether or not their deletion includes the TCF4 gene. It may be difficult to answer this question. In most cases, 18q- was diagnosed using a routine chromosome analysis. This type of analysis can only give a general idea of the location of the deletion’s breakpoint. It cannot tell us precisely which genes are or are not deleted. In order to have this information, a more specialized test, called a microarray analysis, is required.
Characteristics of PHS
Development and Behavior
PHS changes the way the brain develops and functions. All individuals with PHS that have been reported in the literature have significant developmental delays. This means that they do not meet certain developmental milestones, such as rolling over and sitting, on time.
People with PHS have mental retardation. Usually, the degree of mental retardation falls into the severe range of impairment. Some people with PHS do not learn how to walk. Nearly all individuals with PHS are not able to speak in full sentences, though some may be able to communicate with hand gestures or single words.
Many of the children that have been diagnosed with PHS have repetitive motions and movements. For example, they may flap their hands, rock themselves, or bang their heads. In general, they are described as having a happy disposition, though some children with PHS may have aggressive tendencies.
Neurologic changes
People with PHS often have some changes in their muscle tone. Most often, they have decreased muscle tone. This is called hypotonia. Changes in muscle tone can lead to other difficulties. For example, infants with low muscle tone may have difficulty eating because the muscles surrounding the mouth are weak. Low muscle tone may also contribute to developmental delays. Physical, occupational, and speech therapy may improve hypotonia.
Seizures are fairly common in people with PHS. If seizures are suspected, a doctor may request an electroencephalogram (EEG). They may also refer the patient to a neurologist to help manage the seizures.
Some individuals with PHS have ataxia. People with ataxia usually have a hard time coordinating the movement of their arms and legs. It may make walking more difficult.
One of the most unique characteristics of PHS is an abnormal breathing pattern. That is, many individuals with PHS have episodes where they breathe more quickly frequently than normal. This may lead to light-headedness, fainting, numbness and tingling in the hands and feet, and abdominal discomfort.
MRI findings
Many people with PHS have changes in the brain that can only be detected with an MRI. The most common change is a small corpus callosum. The corpus callosum is a bundle of nerves that connects the left and the right side of the brain. This can be associated with some of the neurological problems described above.
Changes in the caudate nucleus have also been reported. The caudate nucleus is a part of the brain involved with learning and memory. The effects of these changes are not well-understood.
Eyes and vision
Vision problems are common in people with PHS. The eyes may be crossed (strabismus). Near-sightedness (myopia) has also been reported.
Because vision problems are possible, people with PHS should have regular eye exams.
Orthopedic
People with PHS may have a curvature of the spine (scoliosis). Foot abnormalities are also fairly common. The most common foot problem is flat feet (pes planus). However, other foot changes have been noted. For example, many people with PHS have small and slender feet.
People with foot or spinal problems may see an orthopedic specialist. Braces and inserts, surgery, and therapy may help in addressing orthopedic concerns.
Genitourinary
Males with PHS may have some changes in the genital region. The testicles may not be fully descended (cryptorchidism). In some cases, this may require surgical correction.
Gastrointestinal
The most common gastrointestinal problem in people with PHS is chronic constipation. This can happen during infancy, childhood, or adults. Medication may help this problem. Another common problem is reflux. Reflux occurs when the stomach contents flow upwards. This can cause pain, irritability, and vomiting. Medication may be helpful for people with reflux. In more severe cases, surgery may be required.
A few conditions have been only been rarely reported in people with PHS. Hirschsprung disease has been reported in one individual. This condition involves a change in the nerves of the large intestines. Pyloric stenosis has also been reported in one person. Pyloric stenosis is a closure or narrowing of the place where the stomach contents enter the intestines.
If there is a concern for gastrointestinal problems, a referral to a gastroenterologist is appropriate.
Growth
In general, people with PHS are shorter than other children and adults of the same age. In addition to short stature, many people with PHS have microcephaly, or a head size that falls below the 3rd percentile.
Facial Features and Other Findings
People with PHS may have facial features that are slightly different from other family members. These changes do not affect a child’s health or development. They are simply small differences that might be noted by a doctor. Their cheekbones might be higher than other family members’. The mouth may be wider and the lip might be shaped a little differently. The teeth might be slightly widely-spaced. The lower part of the face might extend slightly beyond the upper part of the face. Although people with PHS may have facial features in common with one another, it is important to remember that they also have features in common with their family members.
Another feature that has been reported in some people with PHS is an extra nipple. These are sometimes called accessory or supernumerary nipples. They have no health implications. In fact, they occur fairly regularly in the general population. That is, they are frequently found in people who do not have a genetic condition.
Family Planning and Genetic Counseling
Many parents wonder, “If we have another child, what is the chance that our next child will have PHS?”
In general, the likelihood that a second child will also have PHS is low. However, there has been one case report in which the mother of a child with PHS was found to have the same genetic change in some of her cells. In this case, there is a significant chance that a second child could be born with PHS.
If you have questions about the implications of a chromosome change for other family members, we recommend contacting a genetics provider.
Additional Support:
The Chromosome 18 Registry & Research Society does not have a separate listserv for families with PHS at this time. However, there is an online forum hosted through Google Groups. You can join the group by visiting this website.
For Additional Information:
The information provided here is general information based on the literature. However, every person and family with PHS is different. Therefore, this information should not replace professional medical advice, diagnosis, or treatment. If you have questions or concerns, you may find it helpful to talk with a clinical geneticist or genetic counselor. You can locate a genetics provider at one of these sites:
GeneTests Clinic Directory
National Society of Genetic Counselors
Selected References:
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.
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.
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.
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.
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.
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.
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.