PITT-HOPKINS SYNDROME

Scientific background

Pitt and Hopkins first described two patients with a developmental disorder, similar appearance and hyperventilation seizures in 1978. From 2007, microdeletions in the 18q21.2 region and then pathogenic variants in TCF4 were reported to cause Pitt-Hopkins syndrome (PTHS).

The following external features are characteristic and become more pronounced with age: deep-set eyes slanting slightly upward and outward, prominent nasal root, slightly curved nasal bridge and flattened nasal tip, flared nostrils, short philtrum, and a prominent chin. Fetal fingertip pads are often present.

Muscle hypotonia is seen in the first year of life and 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. Speech development is severely impaired or absent with many affected individuals knowing only a few words. Their mood is usually described as cheerful. Repetitive hand movements such as waving or clapping are frequently observed. About 60% have episodes of hyperventilation and/or apnea while awake that are not related to epileptic activity and almost half of the patients have epilepsy. Severe congenital malformations are rare, and chronic constipation is often present. Growth is usually unaffected, and about one-third develop microcephaly. MRI may reveal a corpus callosum deficiency and ventricular dilation. Half of the children have myopia or strabismus.

Differential diagnoses include Angelman syndrome and Mowat-Wilson syndrome, as well as 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 in the CNS.

As pathogenic variants and deletions in TCF4 usually occur de novo, the recurrence risk for siblings is low unless a somatic or germ cell mosaic has been detected in one parent.

References

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