How to Conquer a Chromosome Abnormality— What is Pitt Hopkins syndrome?

University of Texas Health Science Center at San Antonio, Department of Pediatrics The Chromosome 18 Clinical Research Center

First—what is a syndrome? Special points of interest:

 Defining a syndrome. It is important to understand the term task is to identify its underlying cause. syndrome. A syndrome is defined by a Once a genetic cause is discovered,  TCF4 and Pitt Hopkins collection of clinical features. It is the syndrome name and the identified What is a syndrome? also identified when it becomes clear genetic cause are often used inter- • A clinically based definition  Dominant and recessive that a certain combination of clinical changeably. This is technically inap- —look alike genes features frequently occur together propriate because the “syndrome” —same medical issues and are therefore presumed to have a describes a series of clinical fea- —same developmental strengths single cause. These clinical features tures—not the underlying cause. and weaknesses may be facial features, medical issues, • Assumed to have the same cause And to complicate things even more, or developmental strengths and weak- one clinically-recognized syndrome nesses. This is often the point at can actually have multiple underlying which a syndrome is named. causes. Once a syndrome is identified, the next

Inside this issue: Pitt Hopkins Syndrome TCF4 and Pitt Hopkins 2 This is the case with Pitt Hopkins syn- Syndrome drome. The constellation of clinical Pitt Hopkins by Recessive 2 characteristics that make up Pitt Hop- Genetic Mechanism kins syndrome can actually be caused by any of three different genetic defects— What is 18q-? 2 three different genes on three different chromosomes. 18q– or Pitt Hopkins? 3 We believe the most common cause of Pitt Hopkins syndrome involves the gene TCF4 located on the large arm of chro- mosome 18. TCF4 causes Pitt Hopkins syndrome by several mechanisms.

How to Conquer a Chromosome Abnormality— Page 2 What is Pitt Hopkins syndrome?

TCF4 and Pitt Hopkins Syndrome

This diagram illustrates the point. The for normal development to occur. risk for having more than one child with top yellow genes depict the normal This defines a dominant condition. Pitt Hopkins Syndrome. state and normal result. One of the Most dominant conditions are inherit- blue genes has a deletion of the TCF4 ed from one parent, but we presume Normal gene so this person will have Pitt that almost all cases of Pitt Hopkins Hopkins syndrome. One of the pink syndrome—with such a significant genes has a mutation (red star) of the clinical presentation—are the result of Disease TCF4 gene so this person will also a new mutation or new deletion in the have Pitt Hopkins syndrome. child and that neither parent had the Disease condition. These families are at low Both copies of TCF4 must be functional

Pitt Hopkins by Recessive Genetic Mechanism

The other two causes of Pitt Hopkins condition and probably have no idea they mutations making us carriers for many syndrome involve genes on other chromo- are a carrier. conditions. “18q– is not a somes—CNTNAP2 (7q35) and NRXN1 (2p16.3). Both of these genes can cause In a recessive condition both copies of the Normal syndrome but is Pitt Hopkins syndrome but by a recessive gene must somehow be defective in order for disease to result. A person with Pitt defined as a deletion genetic mechanism. Hopkins syndrome caused by one of these Normal (carrier) of a portion of At the top of the diagram to the right, two two recessive genes is likely to have normal copies of the gene are shown chromosome 18. parents who are both carriers of the resulting in no disease. disease. These families are at risk for Normal (carrier) There are no uniform having more children with Pitt Hopkins In a recessive condition, neither the dele- syndrome and should see a genetic coun- Disease deleted regions or tion or mutation of one of the two genes selor for a consultation. By the way, each causes disease. However, people with sets of clinical of us is probably harboring 200 recessive these DNA changes are carriers for the characteristics.”

What is 18q–?

18q– is not a syndrome. But if you look at indi- It is not defined by any viduals 175, 181 and 127, clinical characteristics they share no deleted at all. It is defined by a region in common. genetic test that identi- Consequently, their fies a deletion of a clinical pictures are portion of the long arm very different. We of chromosome 18. All have studied almost persons with 18q– have 300 persons with 18q– different deleted regions and sizes of This diagram illustrates this point. All these and no two unrelated people have the deletions. This means that there is no persons have 18q-. Each blue bar indicates exact same deletion—so no two people characteristic clinical picture for 18q-. the region of the intact chromosome for each would be expected to have the exact same Consequently, people with 18q deletions individual in comparison to the picture of the characteristics as a result of their dele- have a very broad range of medical issues complete chromosome shown across the top. tions; though they may have overlapping and abilities. For example, IQs range from The gaps in the blue lines show the regions of general features, such as developmental 120, which is well above average, to im- their deletions. Their unique study ID num- delays or hypotonia. measurably low. bers are shown on the left. How to Conquer a Chromosome Abnormality— Page 3 What is Pitt Hopkins syndrome?

18q– or Pitt Hopkins?

People whose deletions include the search. However they may not be large deletions of 18q that include TCF4 gene can be thought of as having allowed to participate in some of the TCF4 are not substantially different “Pitt Hopkins syndrome” because their Pitt Hopkins research because their from those with deletions of TCF4 characteristics are similar to persons deletions involve genes in addition to alone. But from a scientific perspec- with Pitt Hopkins. However, technical- TCF4. tive, these persons do not have Pitt ly speaking, none of them have Pitt Hopkins syndrome, as it is defined by a We have found that those persons with Hopkins syndrome. In this illustration, deletion of or mutation on TCF4 alone. “For families, there individuals 30, 181 and 239 all is little distinction have deletions that include TCF4 as well as other genes. Therefore between those technically, they have 18q-. But persons with anything we learn about Pitt deletions of TCF4 Hopkins syndrome will probably apply to these three individuals. only and those So they are likely to benefit from persons with any Pitt Hopkins syndrome re- TCF4 deletions in include TCF4.”

For more information, you may contact the authors and principal investigators of the Chromosome 18 Clinical UTHSCSA—Department of Pediatrics The Chromosome 18 Clinical Research Center Research Center at the phone numbers or email shown to the left. MSC 7820 7703 Floyd Curl Drive Authors & Principal Investigators: San Antonio, TX 78229-3900 Jannine D. Cody, PhD and Daniel E. Hale, MD Phone: 210-567-5321 Fax: 210-567-0919 E-mail: [email protected] Information provided by The Chromosome 18 Clinical Our Motto Research Center to: To provide individuals and families affected by chromosome 18 abnormalities with comprehensive medical and educational information with a focus on treatment options.

We are on the web! http://pediatrics.uthscsa.edu/centers/chromosome18/ http://www.chromosome18.org/ 210-657-4968