We now have the first-ever clinical guidelines for children and adults with Pitt-Hopkins syndrome. The recommendations in these guidelines aim to improve a doctor’s judgement of signs and symptoms in someone with PTHS and to better support carers and families to look after a child or adult with PTHS.

The recommendations on how to clinically diagnose PTHS allow this to be done by doctors anywhere, by looking at specific signs and symptoms, whether or not they have access to modern technology. 

We realise that local circumstances such as medicine-related legal systems (medicolegal environments) may cause changes to the recommendations. Together with the various national PTHS support groups we aim to review the guidelines from time to time, to improve the recommendations.

As a result of the first PTHS World Conference, where these guidelines were created, we identified some major issues for further research:

– What is the natural history of Pitt-Hopkins syndrome in adults and older individuals?

– Breathing anomalies: what are the long-term consequences of breathing anomalies, both physically and cognitively? How prevalent is obstructive sleep apnoea? Can breathing anomalies be decreased if needed?

– Seizures: are seizures primary or consequences of breathing anomalies?

– Other symptoms caused by problems with the autonomic nervous system: what is the exact pathogenesis? If needed, can consequences (especially drooling and constipation) be influenced?

– Immune system: what are the consequences of PTHS variants causing Pitt-Hopkins syndrome for immunological functioning, including reactions to vaccination?

– Motor functioning: what is the pathogenesis of the foot position anomalies? Can physical therapy, drugs or surgical procedures effectively influence these anomalies?

– Communication: what are the communication abilities? Are there biomarkers that predict these abilities? Which approach best increases communicative abilities?

– Behaviour: what are the specific characteristics of autism or autism spectrum disorder in individuals with Pitt-Hopkins syndrome? In which way do factors such as autonomic dysregulations, food or other environmental factors influence behaviour?

Is it possible to address behavioural difficulties effectively through psychotherapy, contextual adjustments and/or drugs if needed?

– Genotype – phenotype correlations

– Molecular characteristics: can a functional study be developed that indicates with sufficient certainty causality of a Pitt-Hopkins phenotype? Can the mRNA derived from the wild type allele be stabilised in vitro? Does this lead to increase protein formation and if so, does this influence the consequences of haplotype insufficiency for TCF4 in animal models?


The authors of the Consensus statement are very grateful to all individuals with PTHS, their parents, and other caregivers who attended the 2018 International PTHS World Conference. The guidelines for lay persons have been translated with great help from Sue and Nathan Routledge and then later revised by an experienced copywriter Charlotte Rastan . Many parents from different countries have helped to translate the guidelines from English into the various other languages, and we are grateful for this.

1. Pitt D, Hopkins I. A syndrome of mental retardation, wide mouth and intermittent overbreathing. Austr Paediatr 1978;14:182-184.

2. Marangi G, Ricciardi S, Orteschi D, et al. The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria. Am J Med Genet 2011;155A:1536–1545, 155.

3. Whalen S, Heron D, Gaillon T, et al. Novel comprehensive diagnostic strategy in Pitt- Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum. Hum Mutat 2012;33:64-72.

 4. De Winter CF, Baas M, Bijlsma EK, et al. Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an Internet questionnaire system. Orphanet J Rare Dis 2016;11:37.

5. Van Balkom IDC, Vuijk PJ, Franssens M, et al. Development, cognition, and behaviour in Pitt–Hopkins syndrome. Develop Med Child Neurol 2012;54:925–931.

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