Diagnosis and management in Pitt‐Hopkins syndrome: First international consensus statement

Abstract

Pitt‐Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.

The first case of a non‐infertile female patient with Pitt–Hopkins syndrome

“…There was no obvious abnormality in the cranial MRI examination of the boy when he was 12 months of age. The boy had a PTHS clinical diagnostic score of 9, which is consistent with the criteria published byZollino et al (2019) for clinical diagnosis of PTHS.A novel heterozygous frameshift variant, c.1973_1974delAC (p.…”

“…It has also been reported that patients with nonspecific mild intellectual disability attributable to TCF4 variants have reproduced successfully. However, there have been no reports of individuals with PTHS with nonmosaic TCF4 variants producing children (Sweetser et al, 1993;Zollino et al, 2019).…”

“…with the criteria published byZollino et al (2019) for the clinical diagnosis of PTHS.The patient had given birth to a boy who was 21 months old at the time of this study. The boy's father was healthy and mental functioning was normal.…”

Behavioural and psychological characteristics in Pitt-Hopkins syndrome: a comparison with Angelman and Cornelia de Lange syndromes

“…PTHS was first identified in 1978 by Pitt and Hopkins [1], who described the syndrome in two unrelated patients presenting with a characteristic facial gestalt (comprising a squared forehead, deep-set eyes, a wide mouth, tented upper lip, full lower lip and a broad and/or beaked nasal bridge), developmental delay and abnormal breathing patterns [2][3][4]. Although the definitive prevalence of PTHS is unknown, prevalence estimates lie between 1 in 225,000 and 1 in 300,000 based on the known number of affected individuals [5].…”

“…[4,6,9,10], see [7] for a review). The first international consensus statement about PTHS [5] draws together current understanding of these with directions for the diagnosis and management of PTHS. The temperament of individuals with PTHS is often described as amiable and happy, characterised by an "easy-going" demeanour (87%) [5,7] and smiling appearance (89%) [4,6].…”