Pitt-Hopkins Syndrome

Excerpt

Clinical characteristics: Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features, significant developmental delays with moderate-to-severe intellectual disability, neurobehavioral/psychiatric manifestations (e.g., stereotypic hand movements, autism spectrum disorder), and autonomic dysfunction (e.g., episodic hyperventilation and/or breath-holding while awake). Speech is significantly affected. Although most individuals are nonverbal, receptive language is often stronger than expressive language. Other common findings are sleep disturbances, seizures, constipation, and severe myopia.

Diagnosis/testing: The diagnosis of PTHS is established in a proband with suggestive findings and one of the following identified by molecular genetic testing: (1) a heterozygous TCF4 pathogenic variant or small intragenic deletions or indels (~70% of affected individuals) or (2) a heterozygous deletion of chromosome 18q21.2 involving TCF4 (~30% of affected individuals).

Management: Treatment of manifestations: Developmental services for infants (physical, occupational, and speech therapies); education tailored to the needs of older children with strong consideration for early training in alternative means of communication; behavioral management strategies; possible treatment of abnormal respiratory pattern; treatment of seizures per neurologist; feeding therapy (for poor weight and persistent feeding issues); physical medicine and rehabilitation, physical therapy, occupational therapy, orthopedics (for treatment of scoliosis if needed); management of bowel dysfunction (gastroesophageal reflux, aspiration risk, constipation as needed) per gastroenterologist; pulmonary medicine (for treatment of respiratory dysregulation as needed).

Surveillance: Ongoing routinely scheduled assessments of development and communication as well as with other specialists providing supportive care to tailor services to individual needs. For older children, develop a plan for transition from pediatric to adult care.

Genetic counseling: PTHS is an autosomal dominant disorder typically caused by a de novo genetic alteration. Rarely, individuals diagnosed with PTHS have the disorder as the result of a genetic alteration inherited from a mosaic parent or, in one family to date, an affected non-mosaic parent. Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.