In 1978, Pitt and Hopkins first described two patients with a developmental disorder, similar appearance, and hyperventilation seizures. In 2007, microdeletions in the 18q21.2 region were first reported to cause Pitt-Hopkins syndrome (PTHS), followed by pathogenic variants in TCF4 shortly after.
The following external features are characteristic and more pronounced with age: deep-set eyes with lid axes rising slightly outward to the top, prominent nasal root, slightly curved nasal bridge and flattened nasal tip, broad nostrils, short philtrum, accentuated chin. Embryonic finger berry pads are often present.
Muscle hypotonia is prominent in the first year of life. Most children are described as “quiet” during this period. A severe global developmental disorder is usually present. On average, affected children learn to walk between the ages of 3 and 4, and speech development is severely impaired to absent with many affected individuals knowing only a few words. The mood is usually described as cheerful. Hand automatisms such as wagging or clapping are frequently observed. About 60% have episodes of hyperventilation and/or apnea only while awake which are not related to epileptic activity. Almost half of the patients have epilepsy. Severe congenital malformations are rare while chronic constipation is often present. Growth is usually unaffected, and about one-third develop microcephaly. MRI may reveal bar deficiency and ventricular dilation. Half of the children have myopia or strabismus.
Differential diagnoses include Angelman syndrome and Mowat-Wilson syndrome but also Rett syndrome and Joubert syndrome.
The prevalence has been estimated at 1:11,000. However, PTHS is probably underdiagnosed.
The disorder is caused by haploinsufficiency of the TCF4 gene in 18q21.2 due to pathogenic variants (approximately 70%) and deletions (approximately 30%). The TCF4 gene has 20 exons, 18 of which are protein-coding (2-19). The TCF4 protein is a transcription factor that is highly expressed in embryonic development including the CNS.
Because pathogenic variants and deletions in TCF4 usually occur de novo, the recurrence risk for siblings is low unless a somatic or germ cell mosaicism has been detected in one parent.
Goodspeed et al. 2018, J Child Neurol 33:233 / Whalen et al. 2012, Hum Mut 33:64 / Ardinger et al. 2012, GeneReviews™ / Marangi et al. 2011, Am J Med Genet 155A:1536 / Amiel et al. 2007, Am J Hum Genet 80:988 / Zweier et al. 2007, Am J Hum Genet 80:994