Scientific background
Pitt-Hopkins syndrome (PTHS) is characterized by developmental disorders, a specific physical appearance, and hyperventilation attacks. It is caused by haploinsufficiency of the TCF4 gene in 18q21.2, with pathogenic variants and microdeletions having been identified. Affected children often show delayed motor and language development, but are frequently described as cheerful. The prevalence is approximately 1:11,000, although the syndrome may be underdiagnosed.
Symptoms
PTHS was first described in 1978 by Pitt and Hopkins in two patients with a developmental disorder, similar appearance and hyperventilation seizures.
The following external features are characteristic and become more pronounced with age:
- Deep-set eyes slanting slightly outward and upward
- Prominent nasal bridge
- Slightly curved nasal bridge and flattened nasal tip
- Flared nostrils
- Short philtrum
- Prominent chin
Persistent fetal fingertip pads are often present.
Muscle hypotonia is noticeable in the first year of life, and most children are described as calm during this period. In most cases, there is a severe global developmental disorder. On average, affected children learn to walk between the ages of 3 and 4. Speech development is severely impaired or absent; many affected children have only a few words in their vocabulary. Their mood is usually described as cheerful. Repetitive hand movements such as waving or clapping are frequently observed.
Around 60% have episodes of hyperventilation and/or apnea when awake, which are not related to epileptic activity. Just under half of patients have epilepsy. Serious congenital malformations are rare. Chronic constipation is often present. Growth is usually unaffected; about one-third develop microcephaly. MRI may reveal a corpus callosum deficiency and ventricular enlargement. Half of the children have myopia or strabismus.
Frequency
The prevalence has been estimated at 1:11,000; however, PTHS is probably underdiagnosed.
Cause
PTHS is caused by haploinsufficiency of the TCF4 gene in 18q21.2 due to pathogenic variants (approx. 70%) and deletions (approx. 30%). The TCF4 gene has 20 exons, 18 of which code for proteins (2-19). The TCF4 protein is a transcription factor that is highly expressed in embryonic development, including in the CNS.
Since pathogenic variants and deletions in TCF4 are usually de novo, the risk of recurrence for siblings is low unless somatic or germline mosaicism has been detected in one parent.
Differential diagnosis
Differential diagnoses include Angelman syndrome and Mowat-Wilson syndrome, as well as Rett syndrome and Joubert syndrome.
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
