Pitt-Hopkins syndrome (18q21 deletion syndrome)

December 31, 2014

Overview

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

Symptoms

People with Pitt-Hopkins syndrome have severe intellectual disability and developmental delay. Most affected individuals do not learn to walk unassisted. People with this condition typically do not develop speech; some may learn to say a few words.

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 within the first decade of life; 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).

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

Causes

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.