Wolf-Hirschhorn syndrome (WHS) happens when a small piece of genetic material is missing from chromosome 4. The missing part is on the short arm of the chromosome, in an area called 4p16.3. Because this piece of DNA is missing, it affects development and causes the features linked to WHS.

In most cases, this happens randomly. The deletion usually occurs when the egg or sperm is being made, or very early after conception during embryonic development. This is called a de novo change, which means it is new in the child and is not caused by a family history of the condition. Around 85–90% of WHS cases happen in this way.

More rarely, WHS can be inherited. This may happen when a parent carries a balanced chromosomal rearrangement, such as a translocation. The parent is usually healthy and may have no symptoms, but the rearrangement can sometimes lead to a missing piece of chromosome 4 in their child.

The amount of missing genetic material can be different from person to person. In general, a larger deletion may be linked to more significant symptoms, but every individual with WHS is unique.