Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Pitt-Hopkins Syndrome (PTHS) [F89.0]

OMIM numbers: 610954, 602272 (TCF4)

Dr. med. Imma Rost, Dr. rer. biol. vet. Ina Vogl

Scientific Background

In 1978, Pitt and Hopkins first described two patients with a developmental disorder, similar appearance and episodes of hyperventilation. As from 2007, microdeletions in the region 18q21.2 were identified as a cause of PTHS, shortly after that, mutations in TCF4.

The following facial features are characteristic - severity increases with age: deep-set eyes with prominence of the supraorbital ridge, high nasal root with prominent nasal bridge, depressed nasal tip, wide nostrils, short philtrum, and pointed chin. Fetal finger pads are common.

Hypotonia occurs within the first year of life; during this time, most children are described as “quiet”. Severe global developmental delay is common. On average, affected children learn to walk between the 3rd and 4th year of life; speech development is severely impaired or absent; many affected patients know only a little amount of words. Mood is frequently being described as bright. Stereotypic hand movements such as waving or clapping are frequently seen. Approx. 60% suffer from episodes of hyperventilation and/or apnea only during waking hours. These episodes have not been associated with epileptic activity. Almost half of all patients have epilepsy. Chronic constipation is common. Severe congenital malformations are rare. Growth is usually not impaired; approx. one third develops microcephaly. MRI may show hypoplasia/agenesis of the corpus callosum as well as ventricular dilation. Half of all children have myopia or strabismus.

Regarding a differential diagnosis, the Angelmann and the Mowat-Wilson syndrome as well as the Rett and the Joubert syndrome should be considered.

Prevalence is estimated to be 1 in 11,000; however, PTHS is most likely underdiagnosed.

The haploinsufficieny of the TCF4 gene in 18q21.2 is causing the disease by mutations (approx. 70%) and deletions (approx. 30%). The TCF4 gene consists of 20 exons, 18 of which are protein-coding (2-19). The TCF4 protein is a transcription factor, which is highly expressed e.g. in the CNS during fetal development.

Since the mutations and the deletions in TCF4 usually occur de novo, the recurrence risk for siblings is low, unless one of the parents was shown to be a carrier of a somatic or a germ cell mosaicism.